PHALY

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PHALY: Phagosome/Lysosome Fusion


 


 


 


 

Stage 1: The System seed

Name
Phagosome/Lysosome Fusion
Code
PHALY
Definition
Control and process of phagosome-lysosome docking and fusion.
Description
Phagosome-lysosome fusion is a key step in autophagy, the process in which a lysosome - a package of acidic, lytic enzymes - fuses to a phagosome that has enveloped some cargo, which is targeted for degradation and recycling. The fusion is a highly regulated process, involving the preparation of lipid microdomains, positioning of vesicles by dynein motors that move along the cytoskeleton, membrane anchored SNAREs that provide core docking functions, the facilitating CORVET, HOPS and BORC complexes, and precise regulation of fusion initiation at the protein level, the lipid level, and through the ionic context which involves calcium-selective voltage gated channels.
Seed term (Biological Process ontology)
Relevant related terms(according to GO graph and co-occurring terms)
Initial associated human genes
 

Seven additional proteins are annotated to GO:0090385 in GOA, they were excluded from the seed-term table because their evidence codes indicated insufficient curation.


 
Seed literature
Corona & Jackson (2018) Finding the Middle Ground for Autophagic Fusion Requirements. Trends Cell Biol 28:869-881. (pmid: 30115558)

[ PubMed ] [ DOI ]

Zhi et al. (2018) Anatomy of autophagy: from the beginning to the end. Cell Mol Life Sci 75:815-831. (pmid: 28939950)

[ PubMed ] [ DOI ]


 

1b: First Sketch

A first sketch of a system architecture that represents components and behaviour in the PHALY system, based on information in two recent reviews[1][2].


 

1c: Observables

 
  • Components
    • Literature curation
    • Annotation to relevant GO terms
  • Collaborations
    • SMART interactions
    • Known complexes
      • SNAREs
      • HOPS Complex
      • BORC complex
    • Crystal structures[3]
  • Behaviour
    • autophagic flux
    • Mislocalization of components
    • genetic interactions
    • Vici syndrome (autosomal recessive EPG5 mutations)


 

Stage 2: Concepts

Concepts

Phagosome - lysosome fusion is the effector step of phagocytosis and (macro)autophagy.

The context of the PHALY system is defined as follows:

  • Phagosome vesicles and lysosome vesicles have been produced and co-localized;
  • The PHALY system docks the two vesicles and fuses their membranes;
  • As a result, lysosome contents gets mixed into the phagosome and its contents is digested.

Fusion is effected by membrane anchored SNARE proteins (soluble NSF attachment protein receptors) in concert with tether complexes that are activated by Rab proteins[1]. SNAREs are small, membrane-anchored, helical proteins that can assemble into four-helix bundles. Based on sequence motifs, SNARES are subdivided into Q-SNARES and R-SNARES. Since parts of the bundle are be located in a vesicle membrane, and other parts in a target membrane, formation of the bundle brings vesicle and target in close proximity. Thus SNAREs are functionally divided into v-SNARES (incoming vesicle, e.g. lysosome), and t-SNARES (target of the vesicle, e.g. phagosome). On the target side, we usually have three Q-SNARE motifs (Qabc); on the vesicle side we usually have a single R-SNARE.

SNAREs alone cannot support efficient fusion. Additional membrane tethers are provided by the HOPS, CORVET and BORC complexes. These complexes are highly regulated by Rab proteins.

Rab proteins are members of one of the five major families of the Ras superfamily[4] (Ras, Rho, Ran, Rab and Arf). These small, homologous GTPases are molecular switches that are localized to specific membrane microdomains. There, they are turned on through a conformational change due to binding GTP, and turned off by hydrolyzing GTP to GDP[5]. These functions are assisted by auxiliary proteins: GAPs (GTPase Activitating Proteins) activate the GTPase activity, thus leading to conversion of GTP to GDP which brings the protein to the off-state, GEF (Guanine nucleotide exchange factors) promote the realease of GDB, followed by binding of GTP which leads to the on-state. Each of the Ras family members has a distinct profile of roles in the cell. The Rab family proteins are predominantly associated with membrane-trafficking and vesicular transport. In the phagosome-lysosome fusion process, Rab proteins are specifically implicated in SNARE/tether protein assembly, and lipid-domain driven localization[3].

To ensure that the fusion happens at the right time in the right place, the system must include

  • functions to synthesize and assemble the required components;
  • localization elements that create a targetable environment and localize the required components in the right place;
  • contact elements that bring all participants into close proximity;
  • on-switches that trigger fusion;
  • components that provide energy and/or metabolites to make fusion proceed against the unfavourable geometry of high-curvature membrane domains;
  • off-switches that limit the fusion event - if this is not a self-limiting process;
  • degradation and recycling functions.


 

Stage 3: Adding Genes

 

Components added from literature review

  • '''CODE''' is the product of ENST12345. Notes. {{#pmid: <PMID>|LABEL}}.
  • '''CODE''' is a component of ''CODE''. Notes. {{#pmid: <PMID>|LABEL}}.
  • '''CODE.<Roman numeral>''' is a state defined by: (COMPONENT CODE.STATE) and [OWN STATE VARIABLE REALIZATION]. {{#pmid: <PMID>|LABEL}}.
  • '''CODE.<Roman numeral>'''changes to (STATE) when [STATE VARIABLE CHANGE]. {{#pmid: <PMID>|LABEL}}.


It is useful to start by collecting facts that are broken down to relate to one single component each. Summarizing knowledge in structured free-text helps parse the facts to enter them into a common data model. The sentence prototype is:

'''COMPONENT''' [SYMBOL] (NAME) is a component of ''SYSTEM''. NOTES. {{#pmid: <PMID>|LABEL}}.

Make special note of genes that are NOT in your system, even though they are homologous to system components or interact with components.


 

Preparing the phagosome

 
  • The autophagosome is a component of the PHALY system. Fusion is the process of joining the outer phagosomal membrane of the autophagosome with the membrane of a lysosome. [1] The outer autophagosomal membrane (OAM) and the inner autophagosomal membrane (IAM) form by membrane fission after closure of the phagosomal sac. [6]
  • The OAM (outer autophagosomal membrane) is a component of the autophagosome system. The outer autophagosomal membrane (OAM) forms by membrane fission after closure of the phagosomal sac. [6]
  • The IAM (inner autophagosomal membrane) is a component of the autophagosome system. The inner autophagosomal membrane (IAM) forms by membrane fission after closure of the phagosomal sac. [6] The IAM is degraded after lysosomal fusion and degradation of the IAM leads to immediate dissociation of STX17 from the cis-SNARE complex. [6]
  • LC3-II is a component of the autophagosome. LC3-II (PE lipidated LC3) has been conjugated to the PE-enriched phagosome membrane and thereby serves as phagosome marker. [1] The LC3-II conjugate is produced by the Atg8 conjugation system (Atg7, Atg3, Atg5, Atg12, Atg16L1/2, Atg4A/B/C/D). [3] Priming of the Atg8 conjugation system requires the Atg12 conjugating system (Atg12, Atg5, Atg7, Atg10) [3]
  • LC3 [MAP1LC3A] (microtubule associated protein 1 light chain 3 alpha) is a component of LC3-II. LC3 is a member of the Atg8 protein family.[1] LC3 is a cytosolic protein that is conjugated to PE in the PE-enriched phagosome membrane in a stress response.[1] Conjugation of LC3 and PE involves a ubiquitin-like conjugation system. [7]
  • PE (phosphatidylethanolamine) is a component of LC3-II. PE is the lipid anchor of LC3 in the phagosome membrane. [1]
  • The SNAP29-STX17 Qabc-SNARE is a component of the SNAP29-STX17-VAMP8 SNARE-pin. The SNAP29-STX17 Qabc-SNARE forms through the interaction of SNAP29 and STX17 in the phagosome membrane.[1]
  • SNAP29 [SNAP29] (synaptosome associated protein 29) is a component of the SNAP29-STX17 Qabc-SNARE. SNAP29 is a Qa-SNARE (a t-SNARE) that localizes to the membrane in a lipidation independent manner through its STX17 interaction. [1] SNAP29 is held in a non-interacting state by O-GlcNAcylation with GlcNAC. [8]
  • GlcNAC (N-acetyl-glucosamine) is a component of the PHALY system. O-GlcNAcylation of SNAP29 in nutrient-sufficient conditions inhibits the association of the SNAP29-STX17 Qabc-SNARE. [1] SNAP29 is O-GlcNAcylated by the promiscuous OGT (UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase) under nutrient-sufficient conditions and thus links the nutrient status sensing system with autophagic flux.[8] SNAP29 has its O-GlcNAcetylation reversed by the N-acetyl-β-glucosaminidase OGA (O-GlcNAcase).[8]
  • STX17 [STX17] (Syntaxin 17) is a component of the SNAP29-STX17 Qabc-SNARE. STX17 is a Qa-SNARE which localizes to the phagosome by binding the phagosome membrane marker LC3-II via its LC3-interacting region (LIR).[1] STX17 phosporylation on S2 is a key decision point for fusion to proceed; dephosphorylation relieves an inhibitory interaction with VPS33A and the phosphomimetic S2E mutant cannot form a SNARE bundle. [9] STX17 has two glycine-zipper motif transmembrane domains that are required for membrane insertion. [10]
  • LAMP2 [LAMP2] (lysosomal associated membrane protein 2) is a component of the PHALY system. LAMP2 is an integral membrane protein. The LAMP-2A isoform has a lysosomal targeting signature sequence. The presence of LAMP2 is required for the binding of STX17.[11]
  • IRGM [IRGM] (immunity related GTPase M) is a component of the PHALY system. IRGM forms a complex (an autophagosome recognition particle, ARP) with STX17 and the Atg8 homologues LC3 and GABARAPL1 that is responsible for phagosomal targeting of STX17. IRGM does not directly bind LC3. IRGM's active conformation is GTP bound. IRGM also has a role in autophagy initiation complexes, binding BECLIN1, ULK1 and ATG16L1, which is indpendent of STX17 binding.[10]
  • RAB7 [RAB7A] (RAB7A, member RAS oncogene family) is a component of the PHALY system. RAB7 is a small GTPase that replaces RAB5 in maturing endosomes.[2] RAB7 localization to the membrane requires prenylation. [1] RAB7 is held in an inactive, soluble state by GDI (ARHGDIA), this interaction - and membrane recruitment - is released by the Mon1-CCZ1 complex.[12] RAB7 is activated on the phagosome by the Mon1-CCZ1 GEF complex which localizes to the phagosome by Atg8 homologue protein binding. [1] RAB7 can be localized to the lysosome by interaction with active lysosomal proton pumping vacuolar-type ATPase (V-ATPase). [13] Inits active conformation, RAB7 can bind RILP to promote minus-end directed microtubular transport of the lysosome towards the MTOC. [14]
  • Mon1-CCZ1 (Mon1-CCZ1 GEF complex) is a component of the PHALY system. The Mon1-CCZ1 GEF complex is a GEF that activates Rab7 by exchanging bound GDP (inactive form) to GTP (active form).[1] It is found on both phagosome and lysosome membranes. [12]
  • MON1A [MON1A] (MON1 homolog A, secretory trafficking associated) is a component of the Mon1-CCZ1 system. MON1A is one of two proteins in the heterooligomeric Mon1-CCZ1 GEF complex. [1]
  • CCZ1 [CCZ1] (CCZ1 homolog, vacuolar protein trafficking and biogenesis associated) is a component of the Mon1-CCZ1 system. CCZ1 is one of two proteins in the heterooligomeric Mon1-CCZ1 GEF complex. [1]
  • GABARAPL1 [GABARAPL1] (GABA type A receptor associated protein like 1) is a component of the PHALY system. GABARAPL1 is a ubiquitin-like modifier that binds to the Mon1-CCZ1 GEF complex and localizes it to the autophagosome.[1] As a yeast Atg8 family homologue (like LC3), GABARAPL1 is a downstream effector of the mTOR pathway. Lipidation by phosphatidylethanolamine causes it to be enriched in the autophagosome membrane, where it serves as a scaffold to recruit other proteins to the membrane. [15]
  • EPG5 [EPG5] (ectopic P-granules autophagy protein 5 homolog) is a component of the PHALY. EPG5 is a RAB7 effector that localizes to both the phagosome and the lysosome by RAB7 binding, and binds to and enhances the SNAP29-STX17 Qabc-SNARE, thus facilitating VAMP8 binding. Binding of EPG5 shifts STX17 affinity from SNAP25 (without EPG5) to SNAP29 (with EPG5). EPG5 mutations cause Vici syndrome. [1]


 

Preparing the lysosome

 
  • The lysosome is a component of the PHALY system. Fusion is the process of joining the outer phagosomal membrane of the phagosome with the membrane of a lysosome. [1]
  • LAMP1 [LAMP1] (lysosomal associated membrane protein 1) is a component of the lysosome. LAMP1 is an integral membrane protein that is a lysosomal marker. [1]
  • VAMP8 [VAMP8] (vesicle associated membrane protein) is a component of the SNAP29-STX17-VAMP8 SNARE-pin. VAMP8 is a component of the lysosome membrane. VAMP8 is the single v-SNARE (an R-SNARE) that is recruited into the Qabc-SNARE complex for fusion. This SNARE "pairing" forms a membrane-bridging trans-SNARE complex, the SNAP29-STX17-VAMP8 SNAREpin. Localization of VAMP8 to the lysosome is dependent on active RAB21. [1]RAB21 activation by SBF2 (a guanine nucleotide exchange factor for GTPases) under starvation conditions is an interface to nutrient sensing. [16]
  • VAMP7 [VAMP7] (vesicle associated membrane protein 7) is a component of the lysosome. The v-SNARE VAMP7 has been considered to be characteristic of secretory lysosomes, i.e. not PHALY.[17] However, VAMP7 interacts with the VPS33A domain of HOPS complex and has been found to be able to initiate fusion with the SNAP29-STX17 Qabc-SNARE by FRET. [9] VAMP7 is part of the SNARE-pin with STX4 and SNAP23 in secretory lysosomes. [18] VAMP7 has an autoinhibitory longin domain that VAMP8 does not have.[19]


 

Tether Proteins and Docking

 
  • The SNAP29-STX17-VAMP8 SNARE-pin is a component of the PHALY system. Binding of the SNAP29-STX17 Qabc-SNARE with VAMP8 forms the initial SNAP29-STX17-VAMP8 SNARE-pin which bridges the phagosome and the lysosome. This trans-SNARE complex (membrane bridging) is the fusion initiator which ultimately leads to "zippering" - membrane apposition, lipid mixing, pore-formation, membrane bilayer fusion, which results in the formation of the cis-SNARE complex (inserted into a single membrane), and bringing the cis-SNARE pin into a alpha-SNAP binding competent conformation. [1][20]
  • ATG14 [ATG14] (Barkor, beclin 1-associated autophagy-related key regulator) is a component of the PIK3C3 complex. ATG14 stimulates BECN1 phosphorylation.[21] ATG14 regulates the PIK3C3 complex.[22]. ATG14 binds to and stabilizes the SNAP29-STX17 Qabc-SNARE on the membrane. [22] ATG14 homooligomers have a membrane-tethering function via their BATS domains (Barkor autophagosome targeting sequence), which is enhanced in membranes with low curvature and high PI(3)P. [22]
  • The HOPS complex (homotypic fusion and protein sorting complex) is a component of the PHALY system. The HOPS complex is a hexa-heterooligomeric membrane tethering complex (MTC complex) that bridges two membranes containing RAB7 molecules in active conformation. It bridges vesicle and target membranes via its Rab7 binding domains and acts as a SNARE chaperone via a SNARE binding domain. It is the major "clamping" factor in SNARE mediated fusion. [2] The chaperoning function is crucial for topologically correct assembly of the trans-SNARE-pin, and prevention of reassembly of a cis-SNARE complex after SNARE disassembly by NSF-SNAP.[23] The BORC complex recruits the HOPS complex to the lysosomal membrane. The BORC complex functions by interacting with kinesins and determining the position of the lysosome by regulating the balance of (+)-end and (-)-end microtubular transport. One of its effectors is Arl8. The BORC complex comprises BLOC1S1, BLOC1S2, SNAPIN, KXD1, BORCS5, BORCS6, BORCS7, and BORCS8. [24]
  • VPS16 [VPS16] (VPS16 core subunit of CORVET and HOPS complexes) is a component of the HOPS complex. VPS16 (Vacuolar Protein Sorting) is one of the four subunits that are common to the HOPS complex and the CORVET complex. It provides part of the SNARE-pin interaction interface. [2]
  • VPS33A [VPS33A] (VPS33A core subunit of CORVET and HOPS complexes) is a component of the HOPS complex. VPS33 (Vacuolar Protein Sorting) is one of the four subunits that are common to the HOPS complex and the CORVET complex. It provides part of the SNARE-pin interaction interface. [2] VPS33A is an SM protein (Sec1/Munc18 protein) which stabilizes the nascent SNARE bundle by interacting with both v-SNARES and t-SNARES. [9] VPS33A interacts with a "closed form of STX17. [9]
  • VPS18 [VPS18] (VPS18 core subunit of CORVET and HOPS complexes) is a component of the HOPS complex. VPS18 (Vacuolar Protein Sorting) is one of the four subunits that are common to the HOPS complex and the CORVET complex. It does not interact with the SNARE-pin. [2]
  • VPS11 [VPS11] (VPS18 core subunit of CORVET and HOPS complexes) is a component of the HOPS complex. VPS11 (Vacuolar Protein Sorting) is one of the four subunits that are common to the HOPS complex and the CORVET complex. It does not interact with the SNARE-pin. [2]
  • VPS41 [VPS41] (VPS41 subunit of HOPS complex) is a component of the HOPS complex. VPS41 (Vacuolar Protein Sorting) is one of the two subunits that are specific to the HOPS complex. It provides one of two Rab7 interaction interfaces. [2]
  • VPS39 [VPS39] (VPS39 subunit of HOPS complex) is a component of the HOPS complex. VPS39 (Vacuolar Protein Sorting) is one of the two subunits that are specific to the HOPS complex. It provides one of two Rab7 interaction interfaces. [2]


 

Lipids

 
  • lipid rafts are a component of the PHALY system. Lipid rafts are required for autophagic flux and play a role in the fusion event. [1]
  • cholesterol is a component of lipid rafts. Cholesterol provides specific binding domains and increases membrane thickness and stiffness. [25]
  • OSBPL1A [OSBPL1A] (Oxysterol binding protein like 1A) is a component of the PHALY system. OSBPL1A is a RAB7-GTP effector. In active form it interacts with cholesterol in lipd rafts through its ORD domain. This interaction recruits PLEKHM1 and through it the HOPS complex. In the absence of cholesterol, OSBPL1A interacts with VAPA via its FFAT domain.[1] This inhibits PLEKHM1 binding to RAB7, whereupon PLEKHM1 and RILP recruit HOPS complex.[14] The ER-bound VAPA protein can be bound by OSBPL1A via its FFAT domain.This interaction creates contact sites between the ER and the phagosome, which inhibits membrane tethers, microtubular transport, and stalls the fusion process.[1]
  • The PIK3C3 complex (RUBCNL-UVRAG–BECN1,2–PIK3C3 complex) is a component of the PHALY system. The PIK3C3 complex creates phosphoinositide-3-phosphate at the phagosome-lysosome fusion site. It integrates a number of general (GPCR) signalling pathways. [25]
  • PIK3C3 [PIK3C3] (phosphatidylinositol 3-kinase catalytic subunit type 3) is a component of the PIK3C3 complex. PIK3C3 (also: Vps34) produces phosphatidylinositol-3-phosphate (PI(3)P) from PI.[26]
  • UVRAG [UVRAG] (UV radiation resistance associated) is a component of the PIK3C3 complex. UVRAG increases RAB7 concentration in maturing endosomes. It provides an interface to the MTORC1 complex: phosporylation of UVRAG by MTORC1 causes it to sequester with RUBCN, away from the HOPS complex.[1]
  • NRBF2 [NRBF2] (nuclear receptor binding factor 2) is a component of the PIK3C3 complex. NRBF2 inhibts PIK3C3 activity and thus reduces PI(3)P levels.[27]
  • PIK3R4 [PIK3R4] (phosphoinositide-3-kinase regulatory subunit 4) is a component of the PIK3C3 complex. PK3R4 (also called Vps15) is a protein kinase that regulates PIK3C3.[28]
  • RUBCN [RUBCN] (rubicon autophagy regulator) is a component of the PIK3C3 complex. RUBCN sequesters UVRAG away from the HOPS complex.[1]
  • RUBCNL [RUBCNL] (rubicon like autophagy enhancer) is a component of the PIK3C3 complex. RUBCNL (Pacer, protein associated with UVRAG as autophagy enhancer) releases UVRAG from RUBCN.[1]. RUBCNL also anchors PI3KC3 as well as HOPS to STX17. Its phosphorylation by mTORC1 integrates the mTOR pathway (active mTOR shuts down RUBCNL enhancement of the system); its acetylation by TIP60 integrates the GSK3-TIP60 pathway. [25]
  • BECN1 [BECN1] (Beclin 1) is a component of the PIK3C3 complex. BECN1 (Beclin1) is a core component of the RUBCNL-UVRAG–BECN1,2–PIK3C3 complex.[1] Phosphorylation of BECN1 is stimulated by ATG14.[21]
  • PLEKHM1 [PLEKHM1] (pleckstrin homology and RUN domain containing M1) is a component of the PIK3C3 complex. PLEKHM1 (Pleckstrin homology domain-containing family M member 1) is a multivalent adaptor that enhances HOPS complex / LC3 (Atg8) interactions in a RAB7 dependent way.[1]
  • PI(3)P (phosphatidylinositol-3-phosphate) is a component of the PIK3C3 complex. PI(3)P interfaces with many signalling pathways. It is produced at the phagosome by PIK3C3 in the PIK3C3 complex, and is further phosphorylated to PI(3,5)P by PIKfyve after dissociation of PIK3C3.[26] Degradation of PI(3)P to PI on phagosomes reduces autophagy.[29]
  • INPP5E [INPP5E] (inositol polyphosphate-5-phosphatase E) is a component of the PHALY system. INPP5E decreases lysosomal phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and increases PI(3)P and is required for the fusion event. Both an excess and a reduction of the PI(3)P to PI(3,5)P2 ratio inhibits fusion.[29]
  • The PIKFYVE complex (PIKFYVE complex) is a component of the PHALY system. The PIKFYVE complex controls PI(3,5)P2 levels and consists of PIKFYVE, FIG4, VAC14 (ArPIKfyve), and WIPI1. [30]
  • PIKFYVE [PIKFYVE] (phosphoinositide kinase, FYVE-type zinc finger containing) is a component of the PIKFYVE complex. PIKFYVE phosphorylates PI(3)P to PI(3,5)P2. Both an excess and a reduction of the PI(3)P to PI(3,5)P2 ratio inhibits fusion. [29]
  • PI(3,5)P2 (phosphatidylinositol-3,5-bisphosphate) is a component of the PIKFYVE complex. (PI(3,5)P2) is produced by the action of PIKFYVE on PI3P. [26] PI(3,5)P2 counteracts cortactin mediated actin filament stabilization on lysosomes; actin on the lysosome surface is required for fusion.[29]


 

Cytoskeleton

 
  • The RAB7-RILP-dynein-dynactin complex (RAB7-RILP-dynein-dynactin complex) is a component of the PHALY system. The RAB7-RILP-dynein-dynactin complex is responsible for minus-end transport of lysosomes along microtubules towards the MTOC, where most lysosomes are located.[14]
  • RILP [RILP] (Rab interacting lysosomal protein) is a component of the RAB7-RILP-dynein-dynactin complex. RILP associates with RAB7-GTP; the complex promotes dynein-dynactin association with the membrane and subsequent transport.[14]
  • An F-actin network (actin filament network) is a component of the PHALY system. A cortactin dependent, remodelled, local filamentous actin network between the phagosome and the lysosome promotes fusion. [7]
  • CTTN [CTTN] (cortactin) is a component of the F-actin network. CTTN is a branch-stabilizing interactor that remodels the F-actin network, which is a fusion requirement by recruiting the ARP2/3 complex to the fusion site.[7]
  • HDAC6 [HDAC6] (histone deacetylase 6) is a component of the F-actin network. HDAC6, a ubiquitin binding deacylase, recruits CTTN to the autophagosome.[7]
  • ARP2/3 complex (ARP2/3 complex) is a component of the F-actin network. The actin-nucleator ARP2/3 complex is a seven-subunit complex that can nucleate actin-filament branchpoints to establish a network. It stimulates the local assembly of an F-actin network for efficient fusion. It consists of ARP2, ARP3, ARPC1, ARPC2, ARPC3, ARPC4, and ARPC5. [7]
  • F-actin (filamentous actin) is a component of the F-actin network. F-actin is a filament of ACTB (G-actin) monomers which is a scaffold for myosin-motors like the fusion-promoting MYO1C myosin to move on. [7]
  • ACTB [ACTB] (actin beta) is a component of F-actin. The cytoplasmic, soluble globular G-actin polymerizes in to a filamentous form: F-actin. [7]
  • MYO1C [MYO1C] (myosin 1C) is a component of the F-actin network. MYO1C is a monomeric class I myosin, which associates with cholesterol lipid rafts. It contains a PH domain that binds specifically to PI(4,5)P2. It is a "slow" motor, ideal for translocating heavy cargos, not tethering, and thus is able to move lipid rafts from storage compartments to their site of action. [7]
  • PI(4,5)P2 (phosphatidylinositol-4,5-bisphosphate) is a component of the F-actin network. PI(4,5)P2 clusters at lipid rafts in a cholesterol and Ca2+ dependent fashion. These clusters bind the ARP2/3 complex. [31]


 

Ion regulation

 
  • Ca2+ (calcium ion) is a component of the PHALY system. Ca2+ is required to stabilize the SNAREpin. [1]
  • CACNA1A [CACNA1A] (Voltage-dependent P/Q-type calcium channel subunit alpha-1A) is a component of the PHALY system. The lysosome resident population of voltage-gated calcium channel CACNA1A is required for calcium efflux from the lysosome for the fusion event. [1]


 

Fusion mechanism

 
  • A SNAREpin team is a component of the PHALY system. From three to six SNAP29-STX17-VAMP8 SNARE-pins form a mechanically coupled SNAREpin team in a rigid membrane (cholesterol lipid-raft) which accelerates fusion by four orders of magnitude. [32]


 

Disassembly and recycling

 
  • The 20s supercomplex is a component of the PHALY system. The 20s supercomplex forms around the cis-SNARE complex, by binding two to four molecules of alpha-SNAP and an NSF homohexamer to the cis-SNARE-pin.[20]
  • alpha-SNAP [NAPA] (NSF attachment protein alpha) is a component of the 20s supercomplex. Two to four molecules of cytoplasmic alpha-SNAP wrap around the cis-SNARE-pin to form a SNAP-SNARE subcomplex. [20]
  • NSF [NSF] (N-ethylmaleimide sensitive factor) is a component of the 20s supercomplex. NSF is a cytoplasmic AAA+ ATPase that binds to the SNAP-SNARE subcomplex in an ATP-bound state. Subsequent ATP hydrolysis induces major conformational rearrangements of NSF that disassociate the SNARE-pin into individual constituent molecules. Nucleotide exchange presumably disassociates the remaining NSF-SNAP subcomplex, and allows the cycle to restart.[20]
  • TBC1D2 [TBC1D2] (TBC1 domain family member 2A) is a component of the PHALY system. TBC1D2 (Armus) is a RAB7 specific GAP that activates hydrolysis of RAB7 bound GTP to GDP and thus catalyzes conversion of RAB7 to its inactive state. [12]


 

Not in the system

 
  • NOT IN PHALY are genes that are not in the PHALY system. "NOT IN PHALY" genes are related to PHALY system components, but are demonstrably not part of PHALY. Genes that are NOT IN PHALY would need to be present in the cell even if the cell did not have a PHALY system. [33]
  • VTI1B [VTI1B] (vesicle transport through interaction with t-SNAREs 1B) is NOT IN PHALY. The t-SNARE VTI1B may work in a pathway that is parallel to STX17, in pathogen containing autophagosomes or recycling endosomes.[1]
  • STX6 [STX6] (syntaxin 6) is NOT IN PHALY. The t-SNARE STX6 is the interaction partner of VTI1B. [1]
  • VAMP3 [VAMP3] (vesicle associated membrane protein 3) is NOT IN PHALY. The v-SNARE VAMP3 forms a SNAREpin with the VTI1B-STX6 complex.[1]


 

Since each of the facts above relates to only one component of the system, they can be imported into an Excel spreadsheet that supports the systems data model. Code is in text2tsv.R on the GitHub repository.

Parallel and/or specialized pathways ...
  • YKT6 may work in a pathway that is parallell to STX17.[1]


Open questions ...
  • Which phospatase dephosphorylates the STX17 N-terminal S2 in the VPS33A complex to switch STX17 into a fusion-competent interaction with HOPS complex? This appears to be a key checkpoint. [9]


 

System hierachy

The Excel spreadsheet has the system and subsystem hierarchy stored in a systemComponent join table. Code to represent this is a tree is in excel2tree.R on the GitHub repository.

 
 --PHALY
   |__20s supercomplex
      |__alpha-SNAP
      |__NSF
   |__autophagosome
      |__IAM
      |__LC3-II
         |__LC3
         |__PE
      |__OAM
   |__Ca2+
   |__CACNA1A
   |__EPG5
   |__F-actin network
      |__ARP2/3 complex
      |__CTTN
      |__F-actin
         |__ACTB
      |__HDAC6
      |__MYO1C
      |__PI(4,5)P2
   |__GABARAPL1
   |__GlcNAC
   |__HOPS complex
      |__VPS11
      |__VPS16
      |__VPS18
      |__VPS33A
      |__VPS39
      |__VPS41
   |__INPP5E
   |__IRGM
   |__LAMP2
   |__lipid rafts
      |__cholesterol
   |__lysosome
      |__LAMP1
      |__VAMP7
   |__Mon1-CCZ1
      |__CCZ1
      |__MON1A
   |__NOT IN PHALY
      |__STX6
      |__VAMP3
      |__VTI1B
   |__OSBPL1A
   |__PIK3C3 complex
      |__ATG14
      |__BECN1
      |__NRBF2
      |__PI(3)P
      |__PIK3C3
      |__PIK3R4
      |__PLEKHM1
      |__RUBCN
      |__RUBCNL
      |__UVRAG
   |__PIKFYVE complex
      |__PI(3,5)P2
      |__PIKFYVE
   |__RAB7
   |__RAB7-RILP-dynein-dynactin complex
      |__RILP
   |__SNAP29-STX17-VAMP8 SNARE-pin
      |__SNAP29-STX17 Qabc-SNARE
         |__SNAP29
         |__STX17
      |__VAMP8
   |__SNAREpin team
   |__TBC1D2


 

Genes added from direct annotation

It is useful to collect links to gene information via the HGNC resource. Code to generate Wikitext for a table with linked information is in text2annotationLinks.R on the GitHub repository.

 

This includes genes discovered because they have been annotated with a relationship to the system, in a database such as UniProt, NCBI-Protein or any of the three GO ontologies represented in GOA (GO annotations).

LC3-II
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
MAP1LC3A microtubule associated protein 1 light chain 3 alpha Q9H492 ENSG00000101460 uc002xaq.3 84557 MAP1LC3A


 
SNAP29-STX17 Qabc-SNARE
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
SNAP29 synaptosome associated protein 29 O95721 ENSG00000099940 uc011ahw.3 9342 SNAP29
STX17 Syntaxin 17 P56962 ENSG00000136874 uc004bal.5 55014 STX17


 
PHALY
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
LAMP2 lysosomal associated membrane protein 2 P13473 ENSG00000005893 uc004ess.5 3920 LAMP2
IRGM immunity related GTPase M A1A4Y4 ENSG00000237693 uc010jhk.3 345611 IRGM
RAB7A RAB7A, member RAS oncogene family P51149 ENSG00000075785 uc003eks.2 7879 RAB7A
GABARAPL1 GABA type A receptor associated protein like 1 Q9H0R8 ENSG00000139112 uc001qxs.4 23710 GABARAPL1
EPG5 ectopic P-granules autophagy protein 5 homolog Q9HCE0 ENSG00000152223 uc002lbm.4 57724 EPG5
OSBPL1A Oxysterol binding protein like 1A Q9BXW6 ENSG00000141447 uc002kve.5 114876 OSBPL1A
INPP5E inositol polyphosphate-5-phosphatase E Q9NRR6 ENSG00000148384 uc004cho.4 56623 INPP5E
CACNA1A Voltage-dependent P/Q-type calcium channel subunit alpha-1A O00555 ENSG00000141837 uc002mwy.5 773 CACNA1A
TBC1D2 TBC1 domain family member 2A Q9BYX2 ENSG00000095383 uc011lvb.3 55357 TBC1D2


 
Mon1-CCZ1
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
MON1A MON1 homolog A, secretory trafficking associated Q86VX9 ENSG00000164077 uc003cxz.4 84315 MON1A
CCZ1 CCZ1 homolog, vacuolar protein trafficking and biogenesis associated P86791 ENSG00000122674 uc003spf.4 51622 CCZ1


 
lysosome
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
LAMP1 lysosomal associated membrane protein 1 P11279 ENSG00000185896 uc001vtm.2 3916 LAMP1
VAMP7 vesicle associated membrane protein 7 P51809 ENSG00000124333 uc004fxj.4 6845 VAMP7


 
SNAP29-STX17-VAMP8 SNARE-pin
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
VAMP8 vesicle associated membrane protein Q9BV40 ENSG00000118640 uc002spt.5 8673 VAMP8


 
PIK3C3 complex
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
ATG14 Barkor, beclin 1-associated autophagy-related key regulator Q6ZNE5 ENSG00000126775 uc001xbx.3 22863 ATG14
PIK3C3 phosphatidylinositol 3-kinase catalytic subunit type 3 Q8NEB9 ENSG00000078142 uc002lap.4 5289 PIK3C3
UVRAG UV radiation resistance associated Q9P2Y5 ENSG00000198382 uc001oxc.4 7405 UVRAG
NRBF2 nuclear receptor binding factor 2 Q96F24 ENSG00000148572 uc001jmj.6 29982 NRBF2
PIK3R4 phosphoinositide-3-kinase regulatory subunit 4 Q99570 ENSG00000196455 uc003enj.4 30849 PIK3R4
RUBCN rubicon autophagy regulator Q92622 ENSG00000145016 NA 9711 RUBCN
RUBCNL rubicon like autophagy enhancer Q9H714 ENSG00000102445 uc001vbi.6 80183 RUBCNL
BECN1 Beclin 1 Q14457 ENSG00000126581 uc002ibn.3 8678 BECN1
PLEKHM1 pleckstrin homology and RUN domain containing M1 Q9Y4G2 ENSG00000225190 uc002ija.4 9842 PLEKHM1


 
HOPS complex
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
VPS16 VPS16 core subunit of CORVET and HOPS complexes Q9H269 ENSG00000215305 uc002whe.5 64601 VPS16
VPS33A VPS33A core subunit of CORVET and HOPS complexes Q96AX1 ENSG00000139719 uc001ucd.4 65082 VPS33A
VPS18 VPS18 core subunit of CORVET and HOPS complexes Q9P253 ENSG00000104142 uc001zne.3 57617 VPS18
VPS11 VPS18 core subunit of CORVET and HOPS complexes Q9H270 ENSG00000160695 uc058iep.1 55823 VPS11
VPS41 VPS41 subunit of HOPS complex P49754 ENSG00000006715 uc003tgy.4 27072 VPS41
VPS39 VPS39 subunit of HOPS complex Q96JC1 ENSG00000166887 uc001zpc.4 23339 VPS39


 
PIKFYVE complex
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
PIKFYVE phosphoinositide kinase, FYVE-type zinc finger containing Q9Y2I7 ENSG00000115020 uc002vcz.3 200576 PIKFYVE


 
RAB7-RILP-dynein-dynactin complex
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
RILP Rab interacting lysosomal protein Q96NA2 ENSG00000167705 uc002ftd.4 83547 RILP


 
F-actin network
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
CTTN cortactin Q14247 ENSG00000085733 uc001opw.5 2017 CTTN
HDAC6 histone deacetylase 6 Q9UBN7 ENSG00000094631 uc004dks.2 10013 HDAC6
MYO1C myosin 1C O00159 ENSG00000197879 uc002fso.4 4641 MYO1C


 
F-actin
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
ACTB actin beta P60709 ENSG00000075624 uc003sot.5 60 ACTB


 
20s supercomplex
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
NAPA NSF attachment protein alpha P54920 ENSG00000105402 uc002pha.3 8775 NAPA
NSF N-ethylmaleimide sensitive factor P46459 ENSG00000073969 uc002iku.4 4905 NSF


 
NOT IN PHALY
 
Symbol Name UniProt ensembl UCSC NCBI gene AmiGO
VTI1B vesicle transport through interaction with t-SNAREs 1B Q9UEU0 ENSG00000100568 uc001xjt.4 10490 VTI1B
STX6 syntaxin 6 O43752 ENSG00000135823 uc021pfr.3 10228 STX6
VAMP3 vesicle associated membrane protein 3 Q15836 ENSG00000049245 uc001aol.3 9341 VAMP3


 


New gene facts:

When we collect new gene facts from databases, we need to be able to annotate the source of a fact, independent of whether it has a pmid. I created a template for this purpose: {{DB|<database>|<ID>}}. For now, it only lists the database, but it will be straightforward to have the template create an actual hyperlink to the record - for a select set of databases.text2tsv.R on the GitHub repository has been modified accordingly.

 
  • ATG13 [ATG13] (autophagy related 13) is a component of the ULK1 complex. Mutations in LC3 can destroy ATG13 interactions and reduce autophagosome formation. (UniProt:Q9H492) ATG13 interacts with LC3 via its LIR (LC3-interacting region). [34] ATG13 is a member of the ULK1 complex which consists of ULK1 (formerly Atg1, unc-51 like autophagy activating kinase 1), ATG13, RB1CC1 (formerly Atg17 / FIP200, RB1 inducible coiled-coil 1), and ATG101. The Atg1 complex is activated under stress conditions by TORC1 and PKA. [34]
  • The ULK1 complex is a component of the autophagosome. The ULK1 complex integrates a large number of cellular systems: the mTOR pathway, AMPK as an effector of AMP homeostasis, growth factor pathways acting via TIP60, genotoxic stress response via PPM1D, protein biosynthesis, and response attenuation during prolonged starvation via the cullin E3 ligase [35].
  • MAP1LC3B [MAP1LC3B] (microtubule associated protein 1 light chain 3 beta) is a component of the LC3-II system. LC3 beta and gamma are functionally equivalent homologues of MAP1LC3A (UCSC:uc002xaq.3).
  • MAP1LC3C [MAP1LC3C] (microtubule associated protein 1 light chain 3 gamma) is a component of the LC3-II system. LC3 beta and gamma are functionally equivalent homologues of MAP1LC3A (UCSC:uc002xaq.3).
  • SNAP23 [SNAP23] (synaptosome associated protein 23) is NOT IN PHALY. SNAP23 is a t-SNARE for general membrane fusion. (UniProt:O00161)
  • SNAP25 [SNAP25] (synaptosome associated protein 25) is NOT IN PHALY. SNAP25 is a t-SNARE involved in neurotransmitter release at the synapse. (UniProt:P61266)
  • STX1A [STX1A] (syntaxin 1A) is NOT IN PHALY. STX1A is involved in hormone and neurotransmitter exocytosis. (UniProt:Q16623)
  • STX1B [STX1B] (syntaxin 1B) is NOT IN PHALY. STX1B is involved in docking of synaptic vesicles at presynaptic active zones. (UniProt:Q16623)
  • STX2 [STX2] (syntaxin 2) is NOT IN PHALY. STX2 is essential for epithelial morphogenesis. (UniProt:P32856)
  • STX3 [STX3] (syntaxin 3) is NOT IN PHALY. STX3 is involved in docking of synaptic vesicles at presynaptic active zones. (UniProt:Q13277)
  • STX4 [STX4] (syntaxin 4) is NOT IN PHALY. STX3 is a plasma mebrane t-SNARE that is involved in docking of transport vesicles. (UniProt:Q12846)
  • STX6 [STX6] (syntaxin 6) is NOT IN PHALY. STX6 is essential involved in vesicle trafficking. (UniProt:O43752)
  • STX7 [STX7] (syntaxin 7) is NOT IN PHALY. STX7 is involved in homotypic fusion of endocytic organelles. (UniProt:O15400)
  • STX8 [STX8] (syntaxin 8) is NOT IN PHALY. STX8 is involved in early-secretory retrograde transport. (UniProt:Q9UNK0)
  • STX10 [STX10] (syntaxin 10) is NOT IN PHALY. STX10 is involved in vesicular transport from the late endosomes to the trans-Golgi network. (UniProt:O60499)
  • STX11 [STX11] (syntaxin 11) is NOT IN PHALY. STX11 acts between the late endosome and the trans-Golgi network. (UniProt:O75558)
  • STX12 [STX12] (syntaxin 12) is NOT IN PHALY. STX12 acts between the late endosome and the trans-Golgi network. (UniProt:Q86Y82)
  • STX16 [STX16] (syntaxin 16) is NOT IN PHALY. STX16 is a t-SNARE localized to the trans-Golgi network. (UniProt:O14662)
  • STX18 [STX18] (syntaxin 18) is NOT IN PHALY. STX18 is a SNARE that is involved in Golgi-derived retrograde transport vesicles. (UniProt:Q9P2W9)
  • STX19 [STX19] (syntaxin 19) is NOT IN PHALY. STX19 is involved in in endosomal trafficking of the epidermal growth factor receptor (EGFR). (UniProt:Q8N4C7)



 

Genes added from network annotation

This includes genes discovered in the network neighbourhood of system components, in a database like STRING or IntAct, or in pathways such as KEGG or Reactome.


New gene facts
  • SEC22B [SEC22B] (SEC22 homolog B, vesicle trafficking protein) is NOT IN PHALY. SEC22B is a high-confidence interactor in STRING, but it is a SNARE that is involved in retrograde transport from the Golgi to the ER. (UniProt:O75396)
  • ATG4A [ATG4A] (autophagy related 4A cysteine peptidase) is a component of LC3-II. ATG4 proteins play a role in Atg8 protein PTM (priming for lipidation) and in delipidation for phagosome disassembly. (KEGG:hsa04140)
  • ATG4B [ATG4B] (autophagy related 4B cysteine peptidase) is a component of LC3-II. ATG4 proteins play a role in Atg8 protein PTM (priming for lipidation) and in delipidation for phagosome disassembly. (KEGG:hsa04140)
  • ATG4C [ATG4C] (autophagy related 4C cysteine peptidase) is a component of LC3-II. ATG4 proteins play a role in Atg8 protein PTM (priming for lipidation) and in delipidation for phagosome disassembly. (KEGG:hsa04140)
  • ATG4D [ATG4D] (autophagy related 4D cysteine peptidase) is a component of LC3-II. ATG4 proteins play a role in Atg8 protein PTM (priming for lipidation) and in delipidation for phagosome disassembly. (KEGG:hsa04140)


 

Genes added from phenotype and behaviour

This includes genes annotated to a related phenotype in OMIM or the GWAS catalog.



 

Completing the Role Ontology

...


 

System Architecture

Sketch a system architecture.


 

System data

Format the system data for import into a system database. Details TBD.

 

JSON formatted data ...  (click to expand)


 

References

  1. ↑ Jump up to: 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35
    Corona & Jackson (2018) Finding the Middle Ground for Autophagic Fusion Requirements. Trends Cell Biol 28:869-881. (pmid: 30115558)

    [ PubMed ] [ DOI ]

  2. ↑ Jump up to: 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8
    Balderhaar & Ungermann (2013) CORVET and HOPS tethering complexes - coordinators of endosome and lysosome fusion. J Cell Sci 126:1307-16. (pmid: 23645161)

    [ PubMed ] [ DOI ]

  3. ↑ Jump up to: 3.0 3.1 3.2 3.3
    Zhi et al. (2018) Anatomy of autophagy: from the beginning to the end. Cell Mol Life Sci 75:815-831. (pmid: 28939950)

    [ PubMed ] [ DOI ]

  4. ↑
    Wennerberg et al. (2005) The Ras superfamily at a glance. J Cell Sci 118:843-6. (pmid: 15731001)

    [ PubMed ] [ DOI ]

  5. ↑
    Goitre et al. (2014) The Ras superfamily of small GTPases: the unlocked secrets. Methods Mol Biol 1120:1-18. (pmid: 24470015)

    [ PubMed ] [ DOI ]

  6. ↑ Jump up to: 6.0 6.1 6.2 6.3
    Tsuboyama et al. (2016) The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354:1036-1041. (pmid: 27885029)

    [ PubMed ] [ DOI ]

  7. ↑ Jump up to: 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7
    Kruppa et al. (2016) Myosins, Actin and Autophagy. Traffic 17:878-90. (pmid: 27146966)

    [ PubMed ] [ DOI ]

  8. ↑ Jump up to: 8.0 8.1 8.2
    Guo et al. (2014) O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation. Nat Cell Biol 16:1215-26. (pmid: 25419848)

    [ PubMed ] [ DOI ]

  9. ↑ Jump up to: 9.0 9.1 9.2 9.3 9.4
    Saleeb et al. (2019) A VPS33A-binding motif on syntaxin 17 controls autophagy completion in mammalian cells. J Biol Chem 294:4188-4201. (pmid: 30655294)

    [ PubMed ] [ DOI ]

  10. ↑ Jump up to: 10.0 10.1
    Kumar et al. (2018) Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins. J Cell Biol 217:997-1013. (pmid: 29420192)

    [ PubMed ] [ DOI ]

  11. ↑
    Hubert et al. (2016) LAMP-2 is required for incorporating syntaxin-17 into autophagosomes and for their fusion with lysosomes. Biol Open 5:1516-1529. (pmid: 27628032)

    [ PubMed ] [ DOI ]

  12. ↑ Jump up to: 12.0 12.1 12.2
    Stroupe (2018) This Is the End: Regulation of Rab7 Nucleotide Binding in Endolysosomal Trafficking and Autophagy. Front Cell Dev Biol 6:129. (pmid: 30333976)

    [ PubMed ] [ DOI ]

  13. ↑
    Matsumoto & Nakanishi-Matsui (2019) Proton pumping V-ATPase inhibitor bafilomycin A1 affects Rab7 lysosomal localization and abolishes anterograde trafficking of osteoclast secretory lysosomes. Biochem Biophys Res Commun 510:421-426. (pmid: 30717974)

    [ PubMed ] [ DOI ]

  14. ↑ Jump up to: 14.0 14.1 14.2 14.3
    Harrison et al. (2003) Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol Cell Biol 23:6494-506. (pmid: 12944476)

    [ PubMed ] [ DOI ]

    Cite error: Invalid <ref> tag; name "Wijdeven2016" defined multiple times with different content Cite error: Invalid <ref> tag; name "Wijdeven2016" defined multiple times with different content Cite error: Invalid <ref> tag; name "Wijdeven2016" defined multiple times with different content
  15. ↑
    Birgisdottir et al. (2019) Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs. Autophagy 15:1333-1355. (pmid: 30767700)

    [ PubMed ] [ DOI ]

  16. ↑
    Jean et al. (2015) Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion. EMBO Rep 16:297-311. (pmid: 25648148)

    [ PubMed ] [ DOI ]

  17. ↑
    Wang et al. (2018) Biomechanical Control of Lysosomal Secretion Via the VAMP7 Hub: A Tug-of-War between VARP and LRRK1. iScience 4:127-143. (pmid: 30240735)

    [ PubMed ] [ DOI ]

  18. ↑
    Spessott et al. (2017) Syntaxin 4 mediates endosome recycling for lytic granule exocytosis in cytotoxic T-lymphocytes. Traffic 18:442-452. (pmid: 28471021)

    [ PubMed ] [ DOI ]

  19. ↑
    Daste et al. (2015) Structure and function of longin SNAREs. J Cell Sci 128:4263-72. (pmid: 26567219)

    [ PubMed ] [ DOI ]

  20. ↑ Jump up to: 20.0 20.1 20.2 20.3
    Zhao et al. (2015) Mechanistic insights into the recycling machine of the SNARE complex. Nature 518:61-7. (pmid: 25581794)

    [ PubMed ] [ DOI ]

  21. ↑ Jump up to: 21.0 21.1
    Fogel et al. (2013) Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy. Mol Cell Biol 33:3675-88. (pmid: 23878393)

    [ PubMed ] [ DOI ]

  22. ↑ Jump up to: 22.0 22.1 22.2
    Diao et al. (2015) ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520:563-6. (pmid: 25686604)

    [ PubMed ] [ DOI ]

  23. ↑
    Baker & Hughson (2016) Chaperoning SNARE assembly and disassembly. Nat Rev Mol Cell Biol 17:465-79. (pmid: 27301672)

    [ PubMed ] [ DOI ]

  24. ↑
    Pu et al. (2015) BORC, a multisubunit complex that regulates lysosome positioning. Dev Cell 33:176-88. (pmid: 25898167)

    [ PubMed ] [ DOI ]

  25. ↑ Jump up to: 25.0 25.1 25.2
    Cheng & Smith (2019) Biological Membrane Organization and Cellular Signaling. Chem Rev 119:5849-5880. (pmid: 30747526)

    [ PubMed ] [ DOI ]

    Cite error: Invalid <ref> tag; name "Cheng2019" defined multiple times with different content Cite error: Invalid <ref> tag; name "Cheng2019" defined multiple times with different content
  26. ↑ Jump up to: 26.0 26.1 26.2
    Naufer et al. (2018) pH of endophagosomes controls association of their membranes with Vps34 and PtdIns(3)P levels. J Cell Biol 217:329-346. (pmid: 29089378)

    [ PubMed ] [ DOI ]

  27. ↑
    Zhong et al. (2014) Nrbf2 protein suppresses autophagy by modulating Atg14L protein-containing Beclin 1-Vps34 complex architecture and reducing intracellular phosphatidylinositol-3 phosphate levels. J Biol Chem 289:26021-37. (pmid: 25086043)

    [ PubMed ] [ DOI ]

  28. ↑
    Lindmo et al. (2008) The PI 3-kinase regulator Vps15 is required for autophagic clearance of protein aggregates. Autophagy 4:500-6. (pmid: 18326940)

    [ PubMed ] [ DOI ]

  29. ↑ Jump up to: 29.0 29.1 29.2 29.3
    Hasegawa et al. (2016) Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome. EMBO J 35:1853-67. (pmid: 27340123)

    [ PubMed ] [ DOI ]

  30. ↑
    Hasegawa et al. (2017) PI5P and PI(3,5)P2: Minor, but Essential Phosphoinositides. Cell Struct Funct 42:49-60. (pmid: 28302928)

    [ PubMed ] [ DOI ]

  31. ↑
    Bucki et al. (2019) Lateral distribution of phosphatidylinositol 4,5-bisphosphate in membranes regulates formin- and ARP2/3-mediated actin nucleation. J Biol Chem 294:4704-4722. (pmid: 30692198)

    [ PubMed ] [ DOI ]

  32. ↑
    Manca et al. (2019) SNARE machinery is optimized for ultrafast fusion. Proc Natl Acad Sci U.S.A 116:2435-2442. (pmid: 30700546)

    [ PubMed ] [ DOI ]

  33. ↑
    Unpublished.
  34. ↑ Jump up to: 34.0 34.1
    Suzuki et al. (2014) Structural basis of the autophagy-related LC3/Atg13 LIR complex: recognition and interaction mechanism. Structure 22:47-58. (pmid: 24290141)

    [ PubMed ] [ DOI ]

  35. ↑
    Zachari & Ganley (2017) The mammalian ULK1 complex and autophagy initiation. Essays Biochem 61:585-596. (pmid: 29233870)

    [ PubMed ] [ DOI ]


 

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