LGG-2 is an LC3-type ATG8 family protein that functions as a ubiquitin-like modifier in autophagy in C. elegans. Unlike its paralog LGG-1 (GABARAP-type), LGG-2 acts downstream in the autophagy pathway, primarily promoting autophagosome maturation and autophagosome-lysosome fusion through direct interaction with the HOPS complex subunit VPS-39. LGG-2 is lipidated (conjugated to phosphatidylethanolamine) at its C-terminal glycine residue, which is essential for membrane association and autophagosome localization. LGG-2 recognizes LIR (LC3-interacting region) motifs in cargo receptors such as SQST-1 and SEPA-1. The protein plays roles in multiple selective autophagy pathways including aggrephagy (degradation of protein aggregates), allophagy (degradation of paternal mitochondria during fertilization), xenophagy (degradation of bacterial toxins), and contributes to apoptotic corpse clearance by facilitating autophagosome-phagosome fusion. LGG-1 and LGG-2 have partially overlapping but distinct functions, with LGG-1 acting upstream to allow LGG-2 localization to autophagosomes, and LGG-2 acting downstream to promote degradation steps.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | ACCEPT | Summary: LGG-2 is recruited to nascent autophagosomes and plays a role in autophagosome biogenesis, though its primary function is downstream in maturation rather than initial assembly. The IBA annotation is phylogenetically sound as ATG8 family members are conserved in this function (PMID:24374177). Reason: ATG8 family proteins including LGG-2 are conjugated to autophagosomal membranes during autophagosome formation. While LGG-2 functions primarily downstream in maturation, it is still involved in the autophagosome assembly process as demonstrated by its localization to autophagosomes and requirement for autophagic flux. The IBA annotation based on phylogeny is appropriate. Supporting Evidence: PMID:24374177 The formation of the autophagic vesicles requires the recruitment of ubiquitin-like Atg8 proteins to the membrane of nascent autophagosomes. PMID:20523114 The formation of the autophagic vesicles requires the recruitment of the Atg8 ubiquitin-like proteins to the membrane of the nascent autophagosomes. |
| GO:0000421 autophagosome membrane | IBA GO_REF:0000033 | ACCEPT | Summary: LGG-2 localizes to autophagosome membranes, where it is conjugated to phosphatidylethanolamine (PE). This localization is well-established experimentally (PMID:24374177, PMID:20523114). Reason: Multiple studies demonstrate LGG-2 localizes to autophagosome membranes in a lipidation-dependent manner. The G130A mutant that cannot be lipidated shows diffuse cytoplasmic localization instead of punctate autophagosomal pattern. Supporting Evidence: PMID:24374177 Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns. PMID:20523114 The C-terminal glycine residue of LGG-2 is essential for post-translational modification and localization to the autophagosomes. |
| GO:0000423 mitophagy | IBA GO_REF:0000033 | ACCEPT | Summary: LGG-2 participates in allophagy, the autophagic degradation of paternal mitochondria after fertilization. This represents a developmentally programmed form of mitophagy in C. elegans (PMID:24374177, PMID:25126728). Reason: The IBA annotation for mitophagy is supported by direct experimental evidence for LGG-2 function in allophagy (degradation of paternal mitochondria during fertilization). LGG-2 is required for degradation of LGG-1-positive allophagic autophagosomes containing paternal organelles. Supporting Evidence: PMID:24374177 During allophagy, a developmentally stereotyped autophagic flux, LGG-1 acts upstream of LGG-2 to allow its localization to autophagosomes. UniProt:Q23536 Involved in allophagy, which is an autophagic process in which paternal mitochondria and organelles are degraded during fertilization |
| GO:0008429 phosphatidylethanolamine binding | IBA GO_REF:0000033 | ACCEPT | Summary: LGG-2 is covalently conjugated to phosphatidylethanolamine (PE) at its C-terminal glycine residue through the ATG7-ATG3 lipidation machinery, which is essential for membrane association (PMID:26687600). Reason: ATG8 family proteins including LGG-2 are lipidated by conjugation to PE. The G130 residue at the C-terminus is the lipidation site. Mutation of G130A abolishes membrane puncta formation, demonstrating the functional importance of PE conjugation. Supporting Evidence: PMID:26687600 Lipidated LGG-1 and LGG-2 possess distinct membrane tethering and fusion activities file:worm/lgg-2/lgg-2-deep-research-falcon.md LGG-2 is synthesized as a precursor, cleaved to expose a C-terminal glycine, and conjugated to phosphatidylethanolamine (PE) by the ATG7-ATG3 machinery |
| GO:0097352 autophagosome maturation | IBA GO_REF:0000033 | ACCEPT | Summary: This is a core function of LGG-2. LGG-2 controls autophagosome maturation and facilitates tethering with lysosomes through interaction with VPS-39 of the HOPS complex (PMID:24374177). Reason: Autophagosome maturation is the primary distinguishing function of LGG-2 compared to LGG-1. LGG-2 acts downstream of LGG-1 to promote maturation and fusion with lysosomes. This is strongly supported by experimental evidence showing LGG-2 interaction with VPS-39/HOPS complex. Supporting Evidence: PMID:24374177 LGG-2 controls the maturation of LGG-1-positive autophagosomes and facilitates the tethering with the lysosomes through a direct interaction with the VPS-39 HOPS complex subunit. |
| GO:0031625 ubiquitin protein ligase binding | IBA GO_REF:0000033 | ACCEPT | Summary: LGG-2 interacts with ATG-7 and ATG-3, which are E1-like and E2-like enzymes in the ubiquitin-like conjugation system that mediates LGG-2 lipidation (PMID:26687600). Reason: ATG8 proteins interact with the ATG7/ATG3 conjugation machinery which has structural similarity to ubiquitin ligases. LGG-2 directly interacts with ATG-7 and ATG-3 for its lipidation, supporting this annotation. Supporting Evidence: PMID:26687600 LGG-1 and LGG-2 interact differentially with autophagy substrates and Atg proteins, many of which carry a LIR motif |
| GO:0006995 cellular response to nitrogen starvation | IBA GO_REF:0000033 | ACCEPT | Summary: Autophagy is induced by starvation conditions including nitrogen starvation. LGG-2 localization is modified during starvation when autophagy is induced (PMID:20523114). Reason: As an essential autophagy factor, LGG-2 participates in the autophagic response to starvation. The IBA annotation based on ATG8 family conservation is appropriate given the universal role of autophagy in nutrient stress response. Supporting Evidence: PMID:20523114 We also demonstrate that the localization of both proteins is modified in several physiological processes when autophagy is induced, namely during diapause "dauer" larval formation, starvation and aging |
| GO:0008017 microtubule binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: This annotation is transferred from mammalian LC3/MAP1LC3 proteins which were originally identified as microtubule-associated protein light chains. However, the microtubule binding function is not the primary or well-characterized function for C. elegans LGG-2. Reason: While mammalian LC3 proteins were named for their association with microtubule-associated proteins, the primary characterized function of LGG-2 in C. elegans is in autophagy, not microtubule binding. There is no direct experimental evidence for LGG-2 microtubule binding in C. elegans. This annotation represents a potential over-extension of the mammalian LC3 nomenclature history rather than a demonstrated function. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: LGG-2 has diffuse cytoplasmic localization in addition to punctate autophagosomal localization (PMID:24374177). Reason: IEA annotation based on UniProt subcellular location is consistent with experimental observations showing cytoplasmic distribution of LGG-2, particularly the unlipidated form. Supporting Evidence: PMID:24374177 Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns |
| GO:0005776 autophagosome | IEA GO_REF:0000120 | ACCEPT | Summary: LGG-2 localizes to autophagosomes when lipidated, forming punctate structures visible by fluorescence microscopy (PMID:24374177, PMID:20523114). Reason: Strong experimental evidence supports LGG-2 localization to autophagosomes. The IEA annotation is consistent with multiple IDA-level observations. Supporting Evidence: PMID:24374177 Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns PMID:20523114 The C-terminal glycine residue of LGG-2 is essential for post-translational modification and localization to the autophagosomes |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: UniProt indicates cell membrane localization based on the lipid anchor. However, the primary localization is to autophagosomal membranes, not the plasma membrane per se. Reason: While LGG-2 is lipid-anchored via PE conjugation, its functional localization is to autophagosomal membranes, not the plasma membrane. The plasma membrane annotation may be an artifact of the lipid-anchor keyword mapping. Experimental studies consistently show autophagosomal, not plasma membrane, localization. Supporting Evidence: PMID:24374177 Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns |
| GO:0006914 autophagy | IEA GO_REF:0000043 | ACCEPT | Summary: LGG-2 is a core autophagy factor, essential for autophagic flux and autophagosome maturation (PMID:24374177, PMID:20523114). Reason: This is a core function. LGG-2 is an ATG8 family protein essential for autophagy. The IEA annotation based on UniProt keyword is well-supported by extensive experimental evidence. Supporting Evidence: PMID:24374177 The formation of the autophagic vesicles requires the recruitment of ubiquitin-like Atg8 proteins to the membrane of nascent autophagosomes. |
| GO:0006950 response to stress | IEA GO_REF:0000117 | ACCEPT | Summary: Autophagy is a stress response pathway. LGG-2 participates in autophagy induced by various stresses including starvation, pathogen infection, and toxic substances (PMID:20523114, PMID:27875098). Reason: This broad annotation is appropriate given LGG-2's role in autophagy, which is a key cellular stress response mechanism. Evidence shows LGG-2 function in response to starvation, aging, and pathogen-derived toxins. Supporting Evidence: PMID:20523114 We also demonstrate that the localization of both proteins is modified in several physiological processes when autophagy is induced, namely during diapause "dauer" larval formation, starvation and aging |
| GO:0016236 macroautophagy | IEA GO_REF:0000117 | ACCEPT | Summary: LGG-2 functions in macroautophagy (canonical autophagy involving double-membrane autophagosome formation), as opposed to other forms of autophagy (PMID:24374177). Reason: LGG-2 is specifically involved in macroautophagy, the double-membrane autophagosome-dependent pathway. This is its core function as an ATG8 family protein that decorates autophagosomal membranes. Supporting Evidence: PMID:24374177 Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | ACCEPT | Summary: LGG-2 localizes to autophagosomes, which are cytoplasmic vesicles. This is a broad parent term of autophagosome. Reason: As an autophagosomal protein, LGG-2 localizes to cytoplasmic vesicles (specifically autophagosomes). This annotation is technically correct though less specific than the autophagosome annotation. Supporting Evidence: PMID:24374177 Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns. |
| GO:0005515 protein binding | IPI PMID:14704431 A map of the interactome network of the metazoan C. elegans. | MODIFY | Summary: High-throughput Y2H interactome study identified LGG-2 protein-protein interactions (PMID:14704431). Reason: The generic "protein binding" term provides little information about LGG-2's actual molecular function. LGG-2 has specific binding functions including LIR motif binding in cargo receptors and interaction with the ATG conjugation machinery. However, the Y2H study identified interaction with ATG-4.1 (atg-4.1), which is the protease that processes ATG8 proteins. A more informative term would be specific to the interaction. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:14704431 Starting with a subset of metazoan-specific proteins, more than 4000 interactions were identified from high-throughput, yeast two-hybrid (HT=Y2H) screens. |
| GO:0005515 protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | MODIFY | Summary: Follow-up high-throughput Y2H interactome study confirmed LGG-2 interactions (PMID:19123269). Reason: Same as above - generic protein binding term is uninformative. The interaction with ATG-4.1 is specific and could be annotated with a more specific term if available. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:19123269 We present an expanded Caenorhabditis elegans protein-protein interaction network, or "interactome" map derived from testing a matrix of ~ 10,000 × ~ 10,000 proteins using a highly specific high-throughput yeast two-hybrid system |
| GO:0097237 cellular response to toxic substance | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: LGG-2 is required for autophagy-mediated defense against the bacterial pore-forming toxin Cry5B. RNAi knockdown of lgg-2 reduces autophagic degradation of membrane pore-forming toxin (PMID:27875098). Reason: Strong experimental evidence shows lgg-2 is required for tolerance to bacterial pore-forming toxin intoxication. This is mediated through autophagy-dependent degradation of the toxin. Supporting Evidence: PMID:27875098 autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously in the PFT-targeted intestinal cells in C. elegans UniProt:Q23536 RNAi-mediated knockdown reduces autophagic degradation of membrane pore-forming toxin Cry5B. |
| GO:0001778 plasma membrane repair | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | KEEP AS NON CORE | Summary: LGG-2/autophagy contributes to repair of plasma membrane pores caused by bacterial pore-forming toxins (PMID:27875098). Reason: While the annotation is experimentally supported, plasma membrane repair is not the core molecular function of LGG-2 - it is a downstream phenotypic consequence of autophagy activity in response to pore-forming toxin damage. The primary function is in autophagy/xenophagy, with membrane repair being a secondary outcome. Supporting Evidence: PMID:27875098 autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously UniProt:Q23536 Also plays a role in membrane-pore repair |
| GO:0098792 xenophagy | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: LGG-2 is required for xenophagic degradation of bacterial pore-forming toxin (PFT) Cry5B (PMID:27875098). Reason: Strong experimental evidence from PMID:27875098 demonstrates that LGG-2 functions in xenophagy to degrade bacterial toxins. This is a specific selective autophagy pathway consistent with LGG-2's role as an ATG8 family autophagy factor. Supporting Evidence: PMID:27875098 autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT UniProt:Q23536 Involved in xenophagy, the autophagy-mediated degradation of pathogens and pathogen products, such as toxins |
| GO:0005515 protein binding | IPI PMID:24374177 The C. elegans LC3 acts downstream of GABARAP to degrade aut... | MODIFY | Summary: LGG-2 interacts with VPS-39, a subunit of the HOPS tethering complex (PMID:24374177). This interaction mediates autophagosome-lysosome fusion. Reason: The interaction with VPS-39 should be captured with a more specific term than generic protein binding. This interaction is functionally important for autophagosome-lysosome tethering and fusion. Proposed replacements: SNARE complex assembly Supporting Evidence: PMID:24374177 LGG-2 controls the maturation of LGG-1-positive autophagosomes and facilitates the tethering with the lysosomes through a direct interaction with the VPS-39 HOPS complex subunit. |
| GO:1901098 positive regulation of autophagosome maturation | IMP PMID:24374177 The C. elegans LC3 acts downstream of GABARAP to degrade aut... | ACCEPT | Summary: This is a core function of LGG-2. LGG-2 positively regulates autophagosome maturation through interaction with VPS-39/HOPS complex (PMID:24374177). Reason: This accurately captures LGG-2's primary distinguishing function - promoting autophagosome maturation and fusion with lysosomes. lgg-2 mutants show defective autophagosome degradation with accumulation of LGG-1-positive autophagosomes. Supporting Evidence: PMID:24374177 LGG-2 controls the maturation of LGG-1-positive autophagosomes and facilitates the tethering with the lysosomes through a direct interaction with the VPS-39 HOPS complex subunit. UniProt:Q23536 Lysosomes have a reduced capacity to interact with autophagosomes in embryos and furthermore, there is defective autophagosome degradation with an accumulation of lgg-1-positive autophagosomes in 500-cell embryos |
| GO:0050830 defense response to Gram-positive bacterium | IEP PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | KEEP AS NON CORE | Summary: lgg-2 expression is upregulated during S. aureus infection as part of HLH-30/TFEB-mediated host defense response (PMID:24882217). Reason: The IEP evidence indicates lgg-2 expression changes during infection, but this reflects autophagy induction as a general host defense mechanism rather than a specific anti-Gram-positive function. The annotation is valid but represents a downstream consequence of autophagy induction by infection, not a core molecular function. Supporting Evidence: PMID:24882217 HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. |
| GO:0000421 autophagosome membrane | IDA PMID:24374177 The C. elegans LC3 acts downstream of GABARAP to degrade aut... | ACCEPT | Summary: Direct experimental evidence shows LGG-2 localizes to autophagosome membranes, forming punctate structures in embryos (PMID:24374177). Reason: IDA evidence directly demonstrates LGG-2 localization to autophagosome membranes through fluorescent reporter imaging. Localization requires ATG-7-dependent lipidation. Supporting Evidence: PMID:24374177 Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns. PMID:24374177 LGG-1 acts upstream of LGG-2 to allow its localization to autophagosomes. |
| GO:0005737 cytoplasm | IDA PMID:20523114 The autophagosomal protein LGG-2 acts synergistically with L... | ACCEPT | Summary: LGG-2 shows cytoplasmic localization in addition to autophagosomal puncta (PMID:20523114). Reason: IDA evidence confirms cytoplasmic localization of LGG-2, particularly the non-lipidated pool. Supporting Evidence: PMID:20523114 During C. elegans development the two proteins share a similar expression pattern and localization but LGG-2 is more abundant in the neurons. |
| GO:0061909 autophagosome-lysosome fusion | IMP PMID:24374177 The C. elegans LC3 acts downstream of GABARAP to degrade aut... | NEW | Summary: LGG-2 promotes autophagosome-lysosome fusion through interaction with VPS-39 of the HOPS tethering complex. This is a core function that distinguishes LGG-2 from LGG-1 (PMID:24374177). Reason: This term precisely captures LGG-2's primary molecular role in promoting autophagosome-lysosome fusion. The evidence shows LGG-2 interacts with VPS-39/HOPS to tether autophagosomes to lysosomes. Supporting Evidence: PMID:24374177 Genetic analyses sustain a sequential implication of LGG-1, LGG-2, RAB-7, and HOPS complex to generate autolysosomes. PMID:24374177 LGG-2 controls the maturation of LGG-1-positive autophagosomes and facilitates the tethering with the lysosomes through a direct interaction with the VPS-39 HOPS complex subunit. |
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Download this section (compressed HTML)Q: What is the functional significance of distinct LGG-1 and LGG-2 positive autophagosome populations during development and stress conditions?
Q: Does LGG-2 have cargo-specific functions distinct from LGG-1 beyond the autophagosome maturation step?
Q: What regulates the sequential handoff from LGG-1 to LGG-2 on autophagosomes?
Experiment: Proteomics to identify LGG-2-specific cargo receptors and interaction partners distinct from LGG-1.
Experiment: Live imaging with dual LGG-1/LGG-2 reporters to characterize the temporal dynamics of ATG8 protein exchange on individual autophagosomes.
Experiment: Structure-function analysis of LGG-2 domains required for VPS-39 interaction and autophagosome-lysosome fusion.
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