MAP1LC3C

MAP1LC3C (LC3C) is an ATG8-family ubiquitin-like protein that drives selective autophagy and, independently, governs lysosomal positioning to exert tumor-suppressive functions (PMID:31851933, PMID:37003503). Like other ATG8 proteins, it is processed at its conserved C-terminal Gly residue and recruited to autophagosome membranes (PMID:12740394); this cleavage depends on a salt bridge between LC3C Arg68 and Asp171 of the cysteine protease ATG4B, which is required for downstream lipidation and autophagosome formation (PMID:23721406). LC3C is structurally distinguished by a unique N-terminal polyproline II 'sticky arm' on a flexible linker in place of the stable α1 helix of other LC3/GABARAP proteins, and phosphorylation of Ser18 at the linker-core interface by PKA remodels its LIR-binding surface (PMID:31578424). Through this surface and adaptor interactions, LC3C executes cargo-selective degradation: it complexes with the MET/HGF receptor tyrosine kinase to route activated, internalized MET into autophagic degradation and restrain MET signaling and cell invasion (PMID:31851933), binds CALCOCO1 to mediate reticulophagy (PMID:31971854), and uses a noncanonical upstream complex (ULK3, UVRAG, RUBCN, PIK3C2A, TSG101) together with its cleaved C-terminal 20-residue peptide to target postdivision midbody rings (PMID:33988680). Independently of its autophagic activity, loss of LC3C drives peripheral lysosome positioning and lysosomal exocytosis, lowering intracellular zinc, reprogramming the transcriptome, and increasing tumor-initiating capacity (PMID:37003503). LC3C does not participate in cardiolipin-mediated mitophagy (PMID:35414338).

1. 2003 Medium

   Establishing that LC3C, despite divergence from LC3B, behaves as a membrane-conjugating ATG8 protein answered whether this isoform is competent for the canonical autophagy lipidation cycle.

   Evidence Cell fractionation and immunofluorescence showing C-terminal cleavage after the conserved Gly and autophagosome membrane association

   PMID:12740394

   Open questions at the time

   • The protease responsible for cleavage was not identified
   • Functional consequences and selectivity of LC3C autophagy were not addressed
2. 2013 Medium

   Defining the LC3C Arg68–ATG4B Asp171 salt bridge explained the molecular requirement for C-terminal processing and connected LC3C to the ATG4B cleavage machinery.

   Evidence Structural simulation, mutagenesis, and autophagic flux assays across ATG8 family members

   PMID:23721406

   Open questions at the time

   • Done by modeling plus mutagenesis without a co-crystal structure of LC3C-ATG4B
   • Did not establish isoform-specific differences in processing kinetics
3. 2019 High

   Solving the unique N-terminal 'sticky arm' architecture and identifying Ser18 PKA phosphorylation revealed how LC3C's adaptor-binding surface can be conformationally regulated, distinguishing it from other LC3/GABARAP proteins.

   Evidence NMR spectroscopy, molecular dynamics simulations, and in vitro PKA kinase assay

   PMID:31578424

   Open questions at the time

   • Ser18 phosphorylation shown in vitro; cellular kinase activity and physiological trigger not established
   • Functional effect on specific cargo selection not tested
4. 2019 High

   Demonstrating LC3C-MET complex formation and LC3C-dependent MET degradation answered how a specific receptor tyrosine kinase is cleared by autophagy and linked LC3C to suppression of invasion.

   Evidence Co-immunoprecipitation, LC3C knockout, domain rescue, and cell invasion assays

   PMID:31851933

   Open questions at the time

   • Direct vs. adaptor-bridged LC3C-MET binding not resolved
   • Single lab; in vivo relevance of MET clearance not established
5. 2020 Medium

   Identifying the LC3C-CALCOCO1 interaction placed LC3C in MTOR-regulated reticulophagy, expanding its selective-autophagy cargo repertoire to the ER.

   Evidence Proteomic and direct interaction validation with CALCOCO1 KO and reticulophagy assays

   PMID:31971854

   Open questions at the time

   • LC3C-specific contribution versus other ATG8 isoforms in reticulophagy not isolated
   • Structural basis of the LC3C-CALCOCO1 LIR interaction not defined
6. 2020 Medium

   Linking LC3C expression to odontogenic differentiation suggested a tissue-specific developmental role beyond bulk autophagy, with isoform selectivity over LC3B.

   Evidence shRNA knockdown and RT-qPCR/protein readout of DMP1 and DSPP markers in human dental pulp cells

   PMID:33230801

   Open questions at the time

   • Mechanism connecting LC3C to odontogenic gene expression unknown
   • Whether the effect depends on autophagy not tested
7. 2021 High

   Defining a noncanonical upstream regulatory complex and the cleaved C-terminal peptide as the targeting determinant for postdivision midbody rings established that LC3C-driven selective autophagy uses dedicated machinery distinct from canonical autophagy.

   Evidence Genetic knockdown/knockout, autophagic flux assays, and domain truncation/sufficiency experiments

   PMID:33988680

   Open questions at the time

   • How the ULK3/UVRAG/RUBCN/PIK3C2A/TSG101 components are assembled and ordered not resolved
   • Direct binding partner of the C-terminal 20-aa peptide on PDMBs not identified
8. 2021 Low

   Reporting that TFG facilitates ULK1-LC3C interaction proposed a bridging factor for omegasome/autophagosome formation under starvation.

   Evidence Co-immunoprecipitation and autophagosome/omegasome formation assays described in a commentary

   PMID:34616872

   Open questions at the time

   • Low-confidence commentary with limited methodological detail; not independently confirmed
   • Direct vs. indirect TFG-LC3C-ULK1 connectivity unclear
9. 2022 Medium

   Testing LC3C in cardiolipin-mediated mitophagy answered whether its lipid-binding extends to mitochondrial cargo recognition, with a clear negative result.

   Evidence In vitro cardiolipin membrane binding, colocalization in SH-SY5Y cells, and siRNA with CCCP/rotenone mitophagy assays

   PMID:35414338

   Open questions at the time

   • Does not exclude LC3C roles in other forms of mitophagy
   • In vitro CL binding without an identified physiological function
10. 2023 Medium

    Separating LC3C's autophagy-dependent and -independent functions revealed an autophagy-independent control of lysosomal positioning and exocytosis that regulates zinc and tumor initiation.

    Evidence Isogenic LC3C-loss cell lines, immunocytochemistry, metabolomics, transcriptomics, and xenograft tumor assays

    PMID:37003503

    Open questions at the time

    • Molecular mechanism by which LC3C controls lysosome positioning not defined
    • Causal chain from zinc changes to PRC2 activity and tumor initiation incompletely mapped
11. 2025 Low

    Connecting LC3C silencing to reduced CIITA and HLA class II proposed a role in antigen-presentation machinery regulation in tumor cells.

    Evidence siRNA/shRNA silencing with CIITA and HLA class II readout by Western blot/RT-qPCR

    PMID:39928678

    Open questions at the time

    • Low-confidence; no direct interaction or reconstitution experiments
    • Mechanism linking LC3C to CIITA transcription unknown
12. 2026 Medium

    Defining an AKT1-scaffold/PDPK1/SQSTM1 axis that loads viral capsids into LC3C-positive phagophores established LC3C participation in antiviral selective autophagy.

    Evidence Genetic KO, phospho-mutant expression, co-immunoprecipitation, and in vivo viral replication assays

    PMID:42152503

    Open questions at the time

    • Direct LC3C-SQSTM1 engagement during capsid loading not fully resolved
    • Generalizability across virus families not established

• How LC3C selects among its diverse cargoes (MET, ER, midbody rings, viral capsids) and how its Ser18 phosphorylation and unique 'sticky arm' tune adaptor choice in cells remain open.
• No integrated model linking sticky-arm conformation to cargo selectivity
• Physiological kinases/phosphatases governing Ser18 in vivo unidentified
• Molecular basis of the autophagy-independent lysosomal positioning function unresolved