Selective MAP1LC3C (LC3C) autophagy requires noncanonical regulators and the C-terminal peptide

LC3s are canonical proteins necessary for the formation of autophagosomes. We have previously established that two paralogs, LC3B and LC3C, have opposite activities in renal cancer, with LC3B playing an oncogenic role and LC3C a tumor-suppressing role. LC3C is an evolutionary late gene present only...

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Bibliographic Details
Published in:The Journal of cell biology 2021-07, Vol.220 (7), p.1
Main Authors: Bischoff, Megan E, Zang, Yuanwei, Chu, Johnson, Price, Adam D, Ehmer, Birgit, Talbot, Nicholas J, Newbold, Michael J, Paul, Anurag, Guan, Jun-Lin, Plas, David R, Meller, Jarek, Czyzyk-Krzeska, Maria F
Format: Article
Language:English
Subjects:
Amino acids
Autophagosomes - genetics
Autophagy
Autophagy - genetics
Autophagy-Related Proteins - genetics
Cancer
Cell Death and Autophagy
DNA-Binding Proteins
Endosomal Sorting Complexes Required for Transport - genetics
Glycine
HeLa Cells
Humans
Microtubule-Associated Proteins - genetics
Peptides
Peptides - genetics
Phagocytosis
Phagosomes
Phosphatidylinositol 3-Kinases - genetics
Protein Serine-Threonine Kinases - genetics
Proteolysis
Stem cell transplantation
Stem cells
Transcription Factors
Tumor Suppressor Proteins - genetics
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Summary:LC3s are canonical proteins necessary for the formation of autophagosomes. We have previously established that two paralogs, LC3B and LC3C, have opposite activities in renal cancer, with LC3B playing an oncogenic role and LC3C a tumor-suppressing role. LC3C is an evolutionary late gene present only in higher primates and humans. Its most distinct feature is a C-terminal 20-amino acid peptide cleaved in the process of glycine 126 lipidation. Here, we investigated mechanisms of LC3C-selective autophagy. LC3C autophagy requires noncanonical upstream regulatory complexes that include ULK3, UVRAG, RUBCN, PIK3C2A, and a member of ESCRT, TSG101. We established that postdivision midbody rings (PDMBs) implicated in cancer stem-cell regulation are direct targets of LC3C autophagy. LC3C C-terminal peptide is necessary and sufficient to mediate LC3C-dependent selective degradation of PDMBs. This work establishes a new noncanonical human-specific selective autophagic program relevant to cancer stem cells.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.202004182