Existing Annotations Review

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.

Core Functions

LGG-2 is conjugated to phosphatidylethanolamine (PE) at its C-terminal glycine (G130) through the ATG7-ATG3 lipidation machinery. This modification is essential for membrane association and autophagosome localization.

Molecular Function:

phosphatidylethanolamine binding

Directly Involved In:

autophagosome maturation autophagosome-lysosome fusion

Cellular Locations:

autophagosome membrane

Supporting Evidence:

PMID:26687600
This protein is subject to lipidation.
PMID:24374177
G->A [at position 130]: Diffuse cytosolic localization in 500-cell embryos with no punctate pattern

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

IBA annotations for ATG8 family functions based on phylogenetic conservation

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:14704431

A map of the interactome network of the metazoan C. elegans.

High-throughput Y2H identified LGG-2 protein interactions including ATG-4.1

"A map of the interactome network of the metazoan C. elegans."

PMID:19123269

Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.

Expanded worm interactome map confirming LGG-2 interactions

"Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network."

PMID:20523114

The autophagosomal protein LGG-2 acts synergistically with LGG-1 in dauer formation and longevity in C. elegans.

LGG-2 is more closely related to human LC3 than LGG-1

"The autophagosomal protein LGG-2 acts synergistically with LGG-1 in dauer formation and longevity in C. elegans."
LGG-2 C-terminal glycine essential for lipidation and autophagosome localization

"The autophagosomal protein LGG-2 acts synergistically with LGG-1 in dauer formation and longevity in C. elegans."
LGG-2 and LGG-1 act synergistically in dauer formation and longevity

"The autophagosomal protein LGG-2 acts synergistically with LGG-1 in dauer formation and longevity in C. elegans."
LGG-2 localization modified during starvation and aging when autophagy induced

"The autophagosomal protein LGG-2 acts synergistically with LGG-1 in dauer formation and longevity in C. elegans."

PMID:24374177

The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39.

LGG-1 acts upstream of LGG-2 during allophagy

"The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39."
LGG-2 controls autophagosome maturation through direct interaction with VPS-39

"The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39."
LGG-2 facilitates autophagosome-lysosome tethering via HOPS complex

"The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39."
Sequential pathway LGG-1 -> LGG-2 -> RAB-7 -> HOPS for autolysosome formation

"The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39."
G130A mutation abolishes autophagosome localization

"The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39."

PMID:24882217

Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes.

HLH-30/TFEB drives expression of autophagy genes including lgg-2 during S. aureus infection

"Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes."
Autophagy genes essential for host tolerance of infection

"Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes."

PMID:27875098

HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans.

LGG-2 required for xenophagic degradation of bacterial pore-forming toxin Cry5B

"HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans."
Autophagy-dependent membrane pore repair

"HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans."
lgg-2 RNAi reduces autophagic degradation of PFT

"HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans."

PMID:26687600

Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy.

Crystal structure of LGG-2 with LIR peptide binding

"Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy."
LGG-2 recognizes LIR motifs in cargo receptors SQST-1, SEPA-1, EPG-2

"Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy."
LGG-2 interacts with ATG-7, ATG-3 for lipidation

"Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy."
LGG-2 interacts with ATG-16.1 and ATG-16.2 WD domains

"Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy."
LGG-2 less effective at promoting membrane fusion than LGG-1

"Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy."

Suggested Experiments

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.

📚 Additional Documentation

Deep Research Falcon

(lgg-2-deep-research-falcon.md)

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gene_id: lgg-2
gene_symbol: lgg-2
uniprot_accession: Q23536
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organism_full: Caenorhabditis elegans.
protein_family: Belongs to the ATG8 family. .
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q23536
Protein Description: RecName: Full=Protein lgg-2;
Gene Information: Name=lgg-2 {ECO:0000312|WormBase:ZK593.6a}; ORFNames=ZK593.6 {ECO:0000312|WormBase:ZK593.6a};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the ATG8 family. .
Key Domains: Atg8-like. (IPR004241); Ubiquitin-like_domsf. (IPR029071); ATG8 (PF02991)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "lgg-2" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'lgg-2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene lgg-2 (gene ID: lgg-2, UniProt: Q23536) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q23536
Protein Description: RecName: Full=Protein lgg-2;
Gene Information: Name=lgg-2 {ECO:0000312|WormBase:ZK593.6a}; ORFNames=ZK593.6 {ECO:0000312|WormBase:ZK593.6a};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the ATG8 family. .
Key Domains: Atg8-like. (IPR004241); Ubiquitin-like_domsf. (IPR029071); ATG8 (PF02991)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "lgg-2" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene lgg-2 (gene ID: lgg-2, UniProt: Q23536) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan summary
- Verified identity: lgg-2 encodes the Caenorhabditis elegans LC3-type Atg8-family protein (UniProt Q23536), a ubiquitin-like protein with a conserved LC3/Atg8 fold and LIR-docking sites. It functions alongside LGG-1 (GABARAP-like) in autophagy and related processes. This aligns with the UniProt description (ATG8 family, ubiquitin-like domains) and the organismal context is C. elegans (no symbol ambiguity detected in the cited literature) (manilsegalen2014thec.elegans pages 2-3, wu2015structuralbasisof pages 4-6, jenzer2019autophagymediatesphosphatidylserine pages 1-5).

Comprehensive research report on lgg-2 (C. elegans; UniProt Q23536)

1) Key concepts and definitions with current understanding
- Protein/gene identity and family: LGG-2 is one of two C. elegans Atg8 homologs; LGG-2 clusters with the LC3 subfamily, while LGG-1 clusters with the GABARAP subfamily. Both decorate autophagosomal membranes and drive autophagy, but with distinct, sequential roles (Developmental Cell, Jan 2014; https://doi.org/10.1016/j.devcel.2013.11.022) (manilsegalen2014thec.elegans pages 2-3).
- Structural features and LIR binding: LGG-2 adopts the conserved Atg8 ubiquitin-like fold and recognizes LC3-interacting region (LIR/AIM) motifs through canonical W- and L-site hydrophobic pockets. Crystal structures revealed LGG-2’s W-site (e.g., Ile33, Pro42, Lys61, Leu63, Phe118) and L-site (e.g., Phe62, Val64, Ile68, Leu73, Ile76, Arg80) that engage LIR peptides; LGG-2’s N-terminus adopts the open (O-form) characteristic of LC3s (Molecular Cell, Dec 17, 2015; https://doi.org/10.1016/j.molcel.2015.11.019) (wu2015structuralbasisof pages 4-6).
- Lipidation and membrane association: Like other Atg8s, LGG-2 is synthesized as a precursor, cleaved to expose a C-terminal glycine, and conjugated to phosphatidylethanolamine (PE) by the ATG7–ATG3 machinery. Mutating the invariant glycine (G130A in LGG-2) abolishes membrane puncta, yielding diffuse reporter signal, demonstrating lipidation is required for membrane association in vivo (Autophagy, Sep 2019; https://doi.org/10.1080/15548627.2018.1512452; eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (jenzer2019autophagymediatesphosphatidylserine pages 21-23, penaramos2022autophagosomesfuseto pages 5-7).

2) Molecular function, pathways, and positioning relative to LGG-1
- Sequential roles in autophagy: LGG-1 (GABARAP-like) acts upstream, and LGG-2 (LC3-like) acts downstream to promote autophagic flux. LGG-2 enables autophagosome degradation by interacting with the HOPS tethering complex subunit VPS39, placing LGG-2 at the autophagosome–lysosome fusion/maturation step (Developmental Cell, Jan 2014; https://doi.org/10.1016/j.devcel.2013.11.022) (manilsegalen2014thec.elegans pages 2-3).
- Selective autophagy and cargo context: Genetic and imaging analyses show cargo- and stage-specific requirements for LGG-2 versus LGG-1. For example, p62/SQST-1::GFP aggregates and other cargo reporters show distinct dependencies across larval stages and tissues, indicating that LGG-2 can be dispensable for certain cargo in early stages but contributes in later or different contexts, consistent with subfamily-specific selectivity (Molecular Cell, Dec 17, 2015; https://doi.org/10.1016/j.molcel.2015.11.019) (wu2015structuralbasisof pages 4-6).
- LAP vs canonical autophagy during apoptotic cell clearance: In C. elegans embryos, LGG-2 participates in the clearance of apoptotic cells, functioning predominantly in phagocytic cells during phagosome maturation/degradation. Both LGG-1 and LGG-2 localizations and functions in this context require canonical autophagy genes (UNC-51/ULK1, BEC-1/BECN1, ATG7), which is unlike mammalian ULK-independent LC3-associated phagocytosis (LAP), supporting the involvement of canonical autophagosomes in corpse clearance (Autophagy, Sep 2019; https://doi.org/10.1080/15548627.2018.1512452) (jenzer2019autophagymediatesphosphatidylserine pages 1-5).
- Autophagosome–phagosome crosstalk: Live imaging shows LGG-2+ autophagosomes are recruited to and fuse with phagosomes containing apoptotic corpses, delivering the inner vesicle into the phagosomal lumen and aiding degradation. This indicates canonical double-membrane autophagosomes, not single-membrane LAP vesicles, facilitate phagosome maturation in C. elegans (eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (penaramos2022autophagosomesfuseto pages 5-7, penaramos2022autophagosomesfuseto pages 11-14).

3) Subcellular localization and dynamics
- Autophagosomes: LGG-2 localizes to punctate, vesicular structures that correspond to double-membrane autophagosomes by EM/immunogold; these puncta require ATG7-mediated lipidation (Developmental Cell, Jan 2014; https://doi.org/10.1016/j.devcel.2013.11.022; eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (manilsegalen2014thec.elegans pages 2-3, penaramos2022autophagosomesfuseto pages 5-7).
- Phagosomes during apoptosis: In embryos, GFP::LGG-2 forms a peripheral, discontinuous ring on phagosomes around apoptotic cells; fluorescence later appears within the lumen after fusion, consistent with autophagosome-phagosome fusion dynamics. Lipidation-defective LGG-2(G130A) remains diffuse and fails to form rings (Autophagy, Sep 2019; https://doi.org/10.1080/15548627.2018.1512452) (jenzer2019autophagymediatesphosphatidylserine pages 21-23, jenzer2019autophagymediatesphosphatidylserine pages 7-10).

4) Phenotypes upon perturbation of lgg-2
- Autophagic flux and development: A deletion allele lgg-2(tm5755) lacks obvious gross developmental defects on its own, but LGG-1 and LGG-2 act synergistically; combined perturbation enhances embryonic defects, consistent with partially redundant/serial functions in autophagy (Developmental Cell, Jan 2014; https://doi.org/10.1016/j.devcel.2013.11.022) (manilsegalen2014thec.elegans pages 2-3).
- Apoptotic corpse clearance: lgg-2 mutants show delayed degradation of engulfed apoptotic corpses (increased persistence of phagosomes/corpses), whereas the timing of engulfment onset is less affected; double lgg-1; lgg-2 mutants give stronger Ced phenotypes, indicating both contribute to efficient clearance but at different steps (Autophagy, Sep 2019; https://doi.org/10.1080/15548627.2018.1512452; eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (jenzer2019autophagymediatesphosphatidylserine pages 7-10, penaramos2022autophagosomesfuseto pages 11-14).

5) Current applications and real-world implementations
- Reporter usage: GFP::LGG-2, mCherry::LGG-2, and mNeonGreen::LGG-2 reporters are widely used to visualize autophagosomes and their dynamics. In phagosome studies, pH-stable red/green reporters allow detection of reporter entry into the acidic phagosomal lumen after fusion, validating fusion events and double-membrane topology (eLife, Jan 2022; https://doi.org/10.7554/eLife.72466). Lipidation-site mutants (LGG-2 G130A) serve as controls to confirm puncta arise from PE conjugation (Autophagy, Sep 2019; https://doi.org/10.1080/15548627.2018.1512452) (penaramos2022autophagosomesfuseto pages 5-7, jenzer2019autophagymediatesphosphatidylserine pages 21-23).
- Autophagosome–phagosome crosstalk assays: Real-time imaging of LGG-2 reporters on phagosomes, combined with autophagy mutants (e.g., atg-7, atg-13, epg-8, atg-9), quantitatively tracks recruitment, fusion, and maturation defects (eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (penaramos2022autophagosomesfuseto pages 5-7, penaramos2022autophagosomesfuseto pages 11-14).

6) Expert opinions and authoritative analyses
- The C. elegans field recognizes two Atg8 homologs with subfamily-specific functions. Consensus from structural and genetic work is that LGG-2 is the LC3-like factor acting later than LGG-1 in autophagic flux and promoting degradation steps via tethering/fusion machinery (HOPS/VPS39), while also playing a defined role in apoptotic corpse processing within phagocytic cells (Developmental Cell, Jan 2014; https://doi.org/10.1016/j.devcel.2013.11.022; Autophagy, Sep 2019; https://doi.org/10.1080/15548627.2018.1512452) (manilsegalen2014thec.elegans pages 2-3, jenzer2019autophagymediatesphosphatidylserine pages 1-5).

7) Recent developments and latest research (prioritized 2022 and notes on 2023–2024)
- 2022 update: High-resolution live imaging demonstrated that LGG-2+ autophagosomes are recruited to and fuse with phagosomes in vivo, providing strong evidence that canonical autophagosomes (not LAP vesicles) facilitate apoptotic corpse degradation in C. elegans (eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (penaramos2022autophagosomesfuseto pages 5-7, penaramos2022autophagosomesfuseto pages 11-14).
- 2023–2024: In the evidence retrieved here, no LGG-2-specific primary study from 2023–2024 was captured. The most recent, directly relevant mechanistic advance for LGG-2 in C. elegans phagosome maturation remains the 2022 eLife study cited above. Earlier foundational work (2014–2019) establishes LGG-2’s LC3-like identity, structural basis for LIR interactions, and downstream fusion/maturation role with HOPS/VPS39 (manilsegalen2014thec.elegans pages 2-3, wu2015structuralbasisof pages 4-6, jenzer2019autophagymediatesphosphatidylserine pages 1-5). If needed, broader Atg8/LC3 reviews from 2023 can contextualize conserved interaction modes, but LGG-2-specific new data were not identified in this evidence set (wu2015structuralbasisof pages 4-6, manilsegalen2014thec.elegans pages 2-3, penaramos2022autophagosomesfuseto pages 5-7).

8) Relevant statistics and data (from recent studies)
- Localization dependency on lipidation: LGG-2(G130A) mutants lose puncta/ring structures and show diffuse signal in embryos clearing apoptotic cells, indicating lipidation is necessary for membrane targeting (Autophagy, Sep 2019; https://doi.org/10.1080/15548627.2018.1512452) (jenzer2019autophagymediatesphosphatidylserine pages 21-23).
- Phagosome maturation timing: In lgg-2 or autophagy mutants (e.g., atg-7), phagosomes persist longer (prolonged lifespans) despite normal engulfment timing, pinpointing LGG-2’s role in maturation/degradation rather than engulfment initiation (eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (penaramos2022autophagosomesfuseto pages 11-14).
- Autophagosome populations: Distinct LGG-1+ and LGG-2+ puncta, and double-positive subsets, decorate phagosome surfaces, reflecting maturation-stage heterogeneity of autophagosomes engaging with phagosomes (eLife, Jan 2022; https://doi.org/10.7554/eLife.72466) (penaramos2022autophagosomesfuseto pages 11-14).

Interpretive synthesis
- Primary function: LGG-2 is a membrane-conjugated LC3-type autophagy factor that binds LIR/AIM-containing partners and promotes autophagosome maturation and degradation steps. In vivo, its most clearly defined role in C. elegans is to promote phagosome maturation during apoptotic corpse clearance by recruiting/fusing canonical autophagosomes to phagosomes, acting downstream of LGG-1/GABARAP and engaging tethering/fusion machinery such as HOPS/VPS39 (manilsegalen2014thec.elegans pages 2-3, penaramos2022autophagosomesfuseto pages 5-7, penaramos2022autophagosomesfuseto pages 11-14).
- Subcellular site of action: LGG-2 acts on autophagosomal membranes and at the phagosomal surface in phagocytic cells; its lipidation-dependent puncta and phagosomal rings reflect membrane association and fusion intermediates (jenzer2019autophagymediatesphosphatidylserine pages 21-23, jenzer2019autophagymediatesphosphatidylserine pages 7-10, manilsegalen2014thec.elegans pages 2-3).
- Pathways: LGG-2 participates in canonical autophagy (ULK/BEC-1/ATG7-dependent) and in autophagosome–phagosome crosstalk for apoptotic corpse degradation. It functions later than LGG-1 and contributes to tethering/fusion with lysosomal machinery via VPS39/HOPS (jenzer2019autophagymediatesphosphatidylserine pages 1-5, manilsegalen2014thec.elegans pages 2-3, penaramos2022autophagosomesfuseto pages 5-7).

Cited sources (URLs and publication dates)
- Manil-Ségalen et al., Developmental Cell 28:43–55, Jan 2014. The C. elegans LC3 Acts Downstream of GABARAP to Degrade Autophagosomes by Interacting with the HOPS Subunit VPS39. URL: https://doi.org/10.1016/j.devcel.2013.11.022 (manilsegalen2014thec.elegans pages 2-3).
- Wu et al., Molecular Cell 60:914–929, Dec 17, 2015. Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy. URL: https://doi.org/10.1016/j.molcel.2015.11.019 (wu2015structuralbasisof pages 4-6).
- Jenzer et al., Autophagy 15:228–241, Sep 2019 (accepted version posted Aug 30, 2018). Autophagy mediates phosphatidylserine exposure and phagosome degradation during apoptosis through specific functions of GABARAP/LGG-1 and LC3/LGG-2. URL: https://doi.org/10.1080/15548627.2018.1512452 (jenzer2019autophagymediatesphosphatidylserine pages 1-5, jenzer2019autophagymediatesphosphatidylserine pages 7-10, jenzer2019autophagymediatesphosphatidylserine pages 21-23).
- Peña-Ramos et al., eLife 11:e72466, Jan 2022. Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells in Caenorhabditis elegans. URL: https://doi.org/10.7554/eLife.72466 (penaramos2022autophagosomesfuseto pages 5-7, penaramos2022autophagosomesfuseto pages 11-14).

Notes on limitations
- Within the collected evidence, 2023–2024 C. elegans LGG-2–specific primary updates were limited; the most recent directly relevant mechanistic data are from 2022 (eLife). Earlier foundational studies remain the primary sources for LGG-2’s structural determinants and pathway placement in C. elegans (penaramos2022autophagosomesfuseto pages 5-7, wu2015structuralbasisof pages 4-6, manilsegalen2014thec.elegans pages 2-3, jenzer2019autophagymediatesphosphatidylserine pages 1-5).

References

(manilsegalen2014thec.elegans pages 2-3): Marion Manil-Ségalen, Christophe Lefebvre, Céline Jenzer, Michael Trichet, Claire Boulogne, Béatrice Satiat-Jeunemaitre, and Renaud Legouis. The c. elegans lc3 acts downstream of gabarap to degrade autophagosomes by interacting with the hops subunit vps39. Developmental Cell, 28:43-55, Jan 2014. URL: https://doi.org/10.1016/j.devcel.2013.11.022, doi:10.1016/j.devcel.2013.11.022. This article has 167 citations and is from a highest quality peer-reviewed journal.
(wu2015structuralbasisof pages 4-6): Fan Wu, Yasunori Watanabe, Xiang-Yang Guo, Xin Qi, Peng Wang, Hong-Yu Zhao, Zheng Wang, Yuko Fujioka, Hui Zhang, Jin-Qi Ren, Tian-Cheng Fang, Yu-Xian Shen, Wei Feng, Jun-Jie Hu, Nobuo N. Noda, and Hong Zhang. Structural basis of the differential function of the two c. elegans atg8 homologs, lgg-1 and lgg-2, in autophagy. Molecular cell, 60 6:914-29, Dec 2015. URL: https://doi.org/10.1016/j.molcel.2015.11.019, doi:10.1016/j.molcel.2015.11.019. This article has 110 citations and is from a highest quality peer-reviewed journal.
(jenzer2019autophagymediatesphosphatidylserine pages 1-5): Céline Jenzer, Elena Simionato, Céline Largeau, Vincent Scarcelli, Christophe Lefebvre, and Renaud Legouis. Autophagy mediates phosphatidylserine exposure and phagosome degradation during apoptosis through specific functions of gabarap/lgg-1 and lc3/lgg-2. Autophagy, 15:228-241, Sep 2019. URL: https://doi.org/10.1080/15548627.2018.1512452, doi:10.1080/15548627.2018.1512452. This article has 33 citations and is from a domain leading peer-reviewed journal.
(jenzer2019autophagymediatesphosphatidylserine pages 21-23): Céline Jenzer, Elena Simionato, Céline Largeau, Vincent Scarcelli, Christophe Lefebvre, and Renaud Legouis. Autophagy mediates phosphatidylserine exposure and phagosome degradation during apoptosis through specific functions of gabarap/lgg-1 and lc3/lgg-2. Autophagy, 15:228-241, Sep 2019. URL: https://doi.org/10.1080/15548627.2018.1512452, doi:10.1080/15548627.2018.1512452. This article has 33 citations and is from a domain leading peer-reviewed journal.
(penaramos2022autophagosomesfuseto pages 5-7): Omar Peña-Ramos, Lucia Chiao, Xianghua Liu, Xiaomeng M. Yu, Tianyou Yao, Henry He, and Zheng Zhou. Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells in caenorhabditis elegans. eLife, Jan 2022. URL: https://doi.org/10.7554/elife.72466, doi:10.7554/elife.72466. This article has 25 citations and is from a domain leading peer-reviewed journal.
(penaramos2022autophagosomesfuseto pages 11-14): Omar Peña-Ramos, Lucia Chiao, Xianghua Liu, Xiaomeng M. Yu, Tianyou Yao, Henry He, and Zheng Zhou. Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells in caenorhabditis elegans. eLife, Jan 2022. URL: https://doi.org/10.7554/elife.72466, doi:10.7554/elife.72466. This article has 25 citations and is from a domain leading peer-reviewed journal.
(jenzer2019autophagymediatesphosphatidylserine pages 7-10): Céline Jenzer, Elena Simionato, Céline Largeau, Vincent Scarcelli, Christophe Lefebvre, and Renaud Legouis. Autophagy mediates phosphatidylserine exposure and phagosome degradation during apoptosis through specific functions of gabarap/lgg-1 and lc3/lgg-2. Autophagy, 15:228-241, Sep 2019. URL: https://doi.org/10.1080/15548627.2018.1512452, doi:10.1080/15548627.2018.1512452. This article has 33 citations and is from a domain leading peer-reviewed journal.

Citations

wu2015structuralbasisof pages 4-6
jenzer2019autophagymediatesphosphatidylserine pages 1-5
jenzer2019autophagymediatesphosphatidylserine pages 21-23
penaramos2022autophagosomesfuseto pages 11-14
penaramos2022autophagosomesfuseto pages 5-7
jenzer2019autophagymediatesphosphatidylserine pages 7-10
https://doi.org/10.1016/j.devcel.2013.11.022
https://doi.org/10.1016/j.molcel.2015.11.019
https://doi.org/10.1080/15548627.2018.1512452;
https://doi.org/10.7554/eLife.72466
https://doi.org/10.1080/15548627.2018.1512452
https://doi.org/10.1016/j.devcel.2013.11.022;
https://doi.org/10.1016/j.devcel.2013.11.022,
https://doi.org/10.1016/j.molcel.2015.11.019,
https://doi.org/10.1080/15548627.2018.1512452,
https://doi.org/10.7554/elife.72466,

📄 View Raw YAML

id: Q23536
gene_symbol: lgg-2
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: 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.
existing_annotations:
- term:
    id: GO:0000045
    label: autophagosome assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: The formation of the autophagic vesicles requires the 
        recruitment of ubiquitin-like Atg8 proteins to the membrane of nascent 
        autophagosomes.
    - reference_id: PMID:20523114
      supporting_text: The formation of the autophagic vesicles requires the 
        recruitment of the Atg8 ubiquitin-like proteins to the membrane of the 
        nascent autophagosomes.
- term:
    id: GO:0000421
    label: autophagosome membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: LGG-2 localizes to autophagosome membranes, where it is conjugated 
      to phosphatidylethanolamine (PE). This localization is well-established 
      experimentally (PMID:24374177, PMID:20523114).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Both LGG-1 and LGG-2 localize to the autophagosomes but 
        display partially overlapping patterns.
    - reference_id: PMID:20523114
      supporting_text: The C-terminal glycine residue of LGG-2 is essential for 
        post-translational modification and localization to the autophagosomes.
- term:
    id: GO:0000423
    label: mitophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: During allophagy, a developmentally stereotyped 
        autophagic flux, LGG-1 acts upstream of LGG-2 to allow its localization 
        to autophagosomes.
    - reference_id: UniProt:Q23536
      supporting_text: Involved in allophagy, which is an autophagic process in 
        which paternal mitochondria and organelles are degraded during 
        fertilization
- term:
    id: GO:0008429
    label: phosphatidylethanolamine binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:26687600
      supporting_text: Lipidated LGG-1 and LGG-2 possess distinct membrane 
        tethering and fusion activities
    - reference_id: file:worm/lgg-2/lgg-2-deep-research-falcon.md
      supporting_text: LGG-2 is synthesized as a precursor, cleaved to expose a 
        C-terminal glycine, and conjugated to phosphatidylethanolamine (PE) by 
        the ATG7-ATG3 machinery
- term:
    id: GO:0097352
    label: autophagosome maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: 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.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:26687600
      supporting_text: LGG-1 and LGG-2 interact differentially with autophagy 
        substrates and Atg proteins, many of which carry a LIR motif
- term:
    id: GO:0006995
    label: cellular response to nitrogen starvation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Autophagy is induced by starvation conditions including nitrogen 
      starvation. LGG-2 localization is modified during starvation when 
      autophagy is induced (PMID:20523114).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20523114
      supporting_text: 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
- term:
    id: GO:0008017
    label: microtubule binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    additional_reference_ids:
    - PMID:24374177
    - PMID:20523114
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: LGG-2 has diffuse cytoplasmic localization in addition to punctate 
      autophagosomal localization (PMID:24374177).
    action: ACCEPT
    reason: IEA annotation based on UniProt subcellular location is consistent 
      with experimental observations showing cytoplasmic distribution of LGG-2, 
      particularly the unlipidated form.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Both LGG-1 and LGG-2 localize to the autophagosomes but 
        display partially overlapping patterns
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: LGG-2 localizes to autophagosomes when lipidated, forming punctate 
      structures visible by fluorescence microscopy (PMID:24374177, 
      PMID:20523114).
    action: ACCEPT
    reason: Strong experimental evidence supports LGG-2 localization to 
      autophagosomes. The IEA annotation is consistent with multiple IDA-level 
      observations.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Both LGG-1 and LGG-2 localize to the autophagosomes but 
        display partially overlapping patterns
    - reference_id: PMID:20523114
      supporting_text: The C-terminal glycine residue of LGG-2 is essential for 
        post-translational modification and localization to the autophagosomes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Both LGG-1 and LGG-2 localize to the autophagosomes but 
        display partially overlapping patterns
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: LGG-2 is a core autophagy factor, essential for autophagic flux and
      autophagosome maturation (PMID:24374177, PMID:20523114).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: The formation of the autophagic vesicles requires the 
        recruitment of ubiquitin-like Atg8 proteins to the membrane of nascent 
        autophagosomes.
- term:
    id: GO:0006950
    label: response to stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20523114
      supporting_text: 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
- term:
    id: GO:0016236
    label: macroautophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: LGG-2 functions in macroautophagy (canonical autophagy involving 
      double-membrane autophagosome formation), as opposed to other forms of 
      autophagy (PMID:24374177).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Both LGG-1 and LGG-2 localize to the autophagosomes but 
        display partially overlapping patterns.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: LGG-2 localizes to autophagosomes, which are cytoplasmic vesicles. 
      This is a broad parent term of autophagosome.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Both LGG-1 and LGG-2 localize to the autophagosomes but 
        display partially overlapping patterns.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14704431
  review:
    summary: High-throughput Y2H interactome study identified LGG-2 
      protein-protein interactions (PMID:14704431).
    action: MODIFY
    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_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:14704431
      supporting_text: Starting with a subset of metazoan-specific proteins, 
        more than 4000 interactions were identified from high-throughput, yeast 
        two-hybrid (HT=Y2H) screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19123269
  review:
    summary: Follow-up high-throughput Y2H interactome study confirmed LGG-2 
      interactions (PMID:19123269).
    action: MODIFY
    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_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:19123269
      supporting_text: "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"
- term:
    id: GO:0097237
    label: cellular response to toxic substance
  evidence_type: IMP
  original_reference_id: PMID:27875098
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:27875098
      supporting_text: 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
    - reference_id: UniProt:Q23536
      supporting_text: RNAi-mediated knockdown reduces autophagic degradation of
        membrane pore-forming toxin Cry5B.
- term:
    id: GO:0001778
    label: plasma membrane repair
  evidence_type: IMP
  original_reference_id: PMID:27875098
  review:
    summary: LGG-2/autophagy contributes to repair of plasma membrane pores 
      caused by bacterial pore-forming toxins (PMID:27875098).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27875098
      supporting_text: autophagy controls the susceptibility of animals to PFT 
        toxicity through xenophagic degradation of PFT and repair of 
        membrane-pore cell-autonomously
    - reference_id: UniProt:Q23536
      supporting_text: Also plays a role in membrane-pore repair
- term:
    id: GO:0098792
    label: xenophagy
  evidence_type: IMP
  original_reference_id: PMID:27875098
  review:
    summary: LGG-2 is required for xenophagic degradation of bacterial 
      pore-forming toxin (PFT) Cry5B (PMID:27875098).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:27875098
      supporting_text: autophagy controls the susceptibility of animals to PFT 
        toxicity through xenophagic degradation of PFT
    - reference_id: UniProt:Q23536
      supporting_text: Involved in xenophagy, the autophagy-mediated degradation
        of pathogens and pathogen products, such as toxins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24374177
  review:
    summary: LGG-2 interacts with VPS-39, a subunit of the HOPS tethering 
      complex (PMID:24374177). This interaction mediates autophagosome-lysosome 
      fusion.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0031593
      label: SNARE complex assembly
    additional_reference_ids:
    - PMID:24374177
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: 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.
- term:
    id: GO:1901098
    label: positive regulation of autophagosome maturation
  evidence_type: IMP
  original_reference_id: PMID:24374177
  review:
    summary: This is a core function of LGG-2. LGG-2 positively regulates 
      autophagosome maturation through interaction with VPS-39/HOPS complex 
      (PMID:24374177).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: 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.
    - reference_id: UniProt:Q23536
      supporting_text: 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
- term:
    id: GO:0050830
    label: defense response to Gram-positive bacterium
  evidence_type: IEP
  original_reference_id: PMID:24882217
  review:
    summary: lgg-2 expression is upregulated during S. aureus infection as part 
      of HLH-30/TFEB-mediated host defense response (PMID:24882217).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24882217
      supporting_text: 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.
- term:
    id: GO:0000421
    label: autophagosome membrane
  evidence_type: IDA
  original_reference_id: PMID:24374177
  review:
    summary: Direct experimental evidence shows LGG-2 localizes to autophagosome
      membranes, forming punctate structures in embryos (PMID:24374177).
    action: ACCEPT
    reason: IDA evidence directly demonstrates LGG-2 localization to 
      autophagosome membranes through fluorescent reporter imaging. Localization
      requires ATG-7-dependent lipidation.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Both LGG-1 and LGG-2 localize to the autophagosomes but 
        display partially overlapping patterns.
    - reference_id: PMID:24374177
      supporting_text: LGG-1 acts upstream of LGG-2 to allow its localization to
        autophagosomes.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20523114
  review:
    summary: LGG-2 shows cytoplasmic localization in addition to autophagosomal 
      puncta (PMID:20523114).
    action: ACCEPT
    reason: IDA evidence confirms cytoplasmic localization of LGG-2, 
      particularly the non-lipidated pool.
    supported_by:
    - reference_id: PMID:20523114
      supporting_text: During C. elegans development the two proteins share a 
        similar expression pattern and localization but LGG-2 is more abundant 
        in the neurons.
- term:
    id: GO:0061909
    label: autophagosome-lysosome fusion
  evidence_type: IMP
  original_reference_id: PMID:24374177
  review:
    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).
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:24374177
      supporting_text: Genetic analyses sustain a sequential implication of 
        LGG-1, LGG-2, RAB-7, and HOPS complex to generate autolysosomes.
    - reference_id: PMID:24374177
      supporting_text: 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.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: IBA annotations for ATG8 family functions based on phylogenetic 
      conservation
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:14704431
  title: A map of the interactome network of the metazoan C. elegans.
  findings:
  - statement: High-throughput Y2H identified LGG-2 protein interactions 
      including ATG-4.1
    supporting_text: A map of the interactome network of the metazoan C. 
      elegans.
- id: PMID:19123269
  title: Empirically controlled mapping of the Caenorhabditis elegans 
    protein-protein interactome network.
  findings:
  - statement: Expanded worm interactome map confirming LGG-2 interactions
    supporting_text: Empirically controlled mapping of the Caenorhabditis 
      elegans protein-protein interactome network.
- id: PMID:20523114
  title: The autophagosomal protein LGG-2 acts synergistically with LGG-1 in 
    dauer formation and longevity in C. elegans.
  findings:
  - statement: LGG-2 is more closely related to human LC3 than LGG-1
    supporting_text: The autophagosomal protein LGG-2 acts synergistically with 
      LGG-1 in dauer formation and longevity in C. elegans.
  - statement: LGG-2 C-terminal glycine essential for lipidation and 
      autophagosome localization
    supporting_text: The autophagosomal protein LGG-2 acts synergistically with 
      LGG-1 in dauer formation and longevity in C. elegans.
  - statement: LGG-2 and LGG-1 act synergistically in dauer formation and 
      longevity
    supporting_text: The autophagosomal protein LGG-2 acts synergistically with 
      LGG-1 in dauer formation and longevity in C. elegans.
  - statement: LGG-2 localization modified during starvation and aging when 
      autophagy induced
    supporting_text: The autophagosomal protein LGG-2 acts synergistically with 
      LGG-1 in dauer formation and longevity in C. elegans.
- id: PMID:24374177
  title: The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes
    by interacting with the HOPS subunit VPS39.
  findings:
  - statement: LGG-1 acts upstream of LGG-2 during allophagy
    supporting_text: The C. elegans LC3 acts downstream of GABARAP to degrade 
      autophagosomes by interacting with the HOPS subunit VPS39.
  - statement: LGG-2 controls autophagosome maturation through direct 
      interaction with VPS-39
    supporting_text: The C. elegans LC3 acts downstream of GABARAP to degrade 
      autophagosomes by interacting with the HOPS subunit VPS39.
  - statement: LGG-2 facilitates autophagosome-lysosome tethering via HOPS 
      complex
    supporting_text: The C. elegans LC3 acts downstream of GABARAP to degrade 
      autophagosomes by interacting with the HOPS subunit VPS39.
  - statement: Sequential pathway LGG-1 -> LGG-2 -> RAB-7 -> HOPS for 
      autolysosome formation
    supporting_text: The C. elegans LC3 acts downstream of GABARAP to degrade 
      autophagosomes by interacting with the HOPS subunit VPS39.
  - statement: G130A mutation abolishes autophagosome localization
    supporting_text: The C. elegans LC3 acts downstream of GABARAP to degrade 
      autophagosomes by interacting with the HOPS subunit VPS39.
- id: PMID:24882217
  title: Innate host defense requires TFEB-mediated transcription of 
    cytoprotective and antimicrobial genes.
  findings:
  - statement: HLH-30/TFEB drives expression of autophagy genes including lgg-2 
      during S. aureus infection
    supporting_text: Innate host defense requires TFEB-mediated transcription of
      cytoprotective and antimicrobial genes.
  - statement: Autophagy genes essential for host tolerance of infection
    supporting_text: Innate host defense requires TFEB-mediated transcription of
      cytoprotective and antimicrobial genes.
- id: PMID:27875098
  title: HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner 
    for epithelium intrinsic cellular defense against bacterial pore-forming 
    toxin in C. elegans.
  findings:
  - statement: LGG-2 required for xenophagic degradation of bacterial 
      pore-forming toxin Cry5B
    supporting_text: HLH-30/TFEB-mediated autophagy functions in a 
      cell-autonomous manner for epithelium intrinsic cellular defense against 
      bacterial pore-forming toxin in C. elegans.
  - statement: Autophagy-dependent membrane pore repair
    supporting_text: HLH-30/TFEB-mediated autophagy functions in a 
      cell-autonomous manner for epithelium intrinsic cellular defense against 
      bacterial pore-forming toxin in C. elegans.
  - statement: lgg-2 RNAi reduces autophagic degradation of PFT
    supporting_text: HLH-30/TFEB-mediated autophagy functions in a 
      cell-autonomous manner for epithelium intrinsic cellular defense against 
      bacterial pore-forming toxin in C. elegans.
- id: PMID:26687600
  title: Structural Basis of the Differential Function of the Two C. elegans 
    Atg8 Homologs, LGG-1 and LGG-2, in Autophagy.
  findings:
  - statement: Crystal structure of LGG-2 with LIR peptide binding
    supporting_text: Structural Basis of the Differential Function of the Two C.
      elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy.
  - statement: LGG-2 recognizes LIR motifs in cargo receptors SQST-1, SEPA-1, 
      EPG-2
    supporting_text: Structural Basis of the Differential Function of the Two C.
      elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy.
  - statement: LGG-2 interacts with ATG-7, ATG-3 for lipidation
    supporting_text: Structural Basis of the Differential Function of the Two C.
      elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy.
  - statement: LGG-2 interacts with ATG-16.1 and ATG-16.2 WD domains
    supporting_text: Structural Basis of the Differential Function of the Two C.
      elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy.
  - statement: LGG-2 less effective at promoting membrane fusion than LGG-1
    supporting_text: Structural Basis of the Differential Function of the Two C.
      elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy.
core_functions:
- molecular_function:
    id: GO:0008429
    label: phosphatidylethanolamine binding
  description: LGG-2 is conjugated to phosphatidylethanolamine (PE) at its 
    C-terminal glycine (G130) through the ATG7-ATG3 lipidation machinery. This 
    modification is essential for membrane association and autophagosome 
    localization.
  supported_by:
  - reference_id: PMID:26687600
    supporting_text: This protein is subject to lipidation.
  - reference_id: PMID:24374177
    supporting_text: 'G->A [at position 130]: Diffuse cytosolic localization in 500-cell
      embryos with no punctate pattern'
  directly_involved_in:
  - id: GO:0097352
    label: autophagosome maturation
  - id: GO:0061909
    label: autophagosome-lysosome fusion
  locations:
  - id: GO:0000421
    label: autophagosome membrane
suggested_questions:
- question: What is the functional significance of distinct LGG-1 and LGG-2 
    positive autophagosome populations during development and stress conditions?
- question: Does LGG-2 have cargo-specific functions distinct from LGG-1 beyond 
    the autophagosome maturation step?
- question: What regulates the sequential handoff from LGG-1 to LGG-2 on 
    autophagosomes?
suggested_experiments:
- description: Proteomics to identify LGG-2-specific cargo receptors and 
    interaction partners distinct from LGG-1.
- description: Live imaging with dual LGG-1/LGG-2 reporters to characterize the 
    temporal dynamics of ATG8 protein exchange on individual autophagosomes.
- description: Structure-function analysis of LGG-2 domains required for VPS-39 
    interaction and autophagosome-lysosome fusion.
tags:
- caeel-mitophagy

lgg-2

Gene Description

Existing Annotations Review

Core Functions

LGG-2 is conjugated to phosphatidylethanolamine (PE) at its C-terminal glycine (G130) through the ATG7-ATG3 lipidation machinery. This modification is essential for membrane association and autophagosome localization.

References

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Suggested Experiments

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

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Research Target:

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