# Mechanisms of selective autophagy

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $321,000

## Abstract

In this proposal we investigate mechanism of selective autophagy in a novel, noncanonical pathway which has
tumor suppressing activity in renal cancer. Autophagy is a tightly regulated process of self-digestion, which in
cancer can have both tumor suppressing and oncogenic activities. Formation of an autophagosome requires
microtubule associated protein 1 light chains A, B and C (MAP1LC3A, B, C referred to as LC3A, B and C). LC3s
bind with cargo receptors through the LC3C-interacting regions (LIR) motifs on the receptors. Clear cell renal
cell carcinoma (ccRCC) is the most frequent renal cancer characterized by the loss the von Hippel-Lindau gene
(VHL). Loss of VHL function leads to activation of Hypoxia Inducible Transcription Factors (HIF) and changes in
angiogenesis and metabolism. Our laboratory discovered that VHL regulates autophagy. VHL inhibits LC3B
autophagy, which is oncogenic in ccRCC. In contrast, VHL induces tumor suppressing, LC3C autophagy in a
mechanism that involves removal of transcription repression by HIF. LC3C is an evolutionary late gene, present
only in higher primates and humans that evolved into multifaceted autophagic regulator, more complicated as
compared to LC3B/A. It maintains binding site for the canonical LIRs, similar to other LC3s, but it gained a new
binding site for LC3C-specific LIR, CLIR, and a highly conserved C-terminal, 20 amino acid peptide, cleaved in
the process of glycine lipidation. Our preliminary results show that LC3C autophagy requires novel non-canonical
pre- and -initiation complexes, which include ULK3, BECN1, UVRAG and PIK3C2A. We identified two direct
targets selectively degraded by LC3C autophagy: (i) Postdivision Midbody Rings (PDMBs), remnants of midbody
structures created during cytokinesis. PDMB accumulation in cancer cells promotes stem-like state and cancer
progression. (ii) Caveolin 1(CAV1), a lipid raft cholesterol-binding protein. We found that LC3C-dependent
degradation of the cargo requires C-terminal peptide on LC3C and a protein complex that includes adapter
proteins, TSG101 and CHMP2B. Surprisingly, VHL interacts with the core autophagy apparatus in an LC3C-
dependent manner, an indication that it directly serves in the formation of LC3C autophagosomes. In Aim 1, we
will determine activity of the LC3C preinitiation, initiation, and adapter complexes. We hypothesize that LC3C
autophagy is regulated by distinctive and selective mediators, as compared to LC3B, of the pre- and initiation
complexes and TSG101 anchors LC3C to the selective cargo. In Aim 2 we will determine the direct role of VHL
in regulation of LC3C autophagy. We propose that VHL anchors at the LC3C regulatory complex through the
hydroxylated proline in the C-terminal peptide and is necessary for the association with the core autophagic
proteins. In Aim 3 we will determine the role of unique structures of LC3C in the selective degradation of cargo
by the non-canonical pathway and in tumor suppressing activity of LC3...

## Key facts

- **NIH application ID:** 10017261
- **Project number:** 5R01GM128216-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Maria F Czyzyk-Krzeska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $321,000
- **Award type:** 5
- **Project period:** 2019-09-12 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017261

## Citation

> US National Institutes of Health, RePORTER application 10017261, Mechanisms of selective autophagy (5R01GM128216-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017261. Licensed CC0.

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