RUNDC1 negatively mediates the fusion of autophagosomes with lysosomes via regulating SNARE complex assembly

Autophagy. 2024 Feb;20(2):454-456. doi: 10.1080/15548627.2023.2274210. Epub 2024 Jan 25.

Abstract

Macroautophagy/autophagy is an essential pro-survival mechanism activated in response to nutrient deficiency. The proper fusion between autophagosomes and lysosomes is a critical step for autophagic degradation. We recently reported that RUNDC1 (RUN domain containing 1) inhibits autolysosome formation via clasping the ATG14-STX17-SNAP29 complex to hinder VAMP8 binding. We showed that RUNDC1 colocalizes with LC3 and associates with mature autophagosomes in cell lines and the zebrafish model. We utilized liposome fusion and in vitro autophagosome-lysosome fusion assays to demonstrate that RUNDC1 inhibits autolysosome formation. Moreover, we found that RUNDC1 clasps the ATG14-STX17-SNAP29 complex via stimulating ATG14 homo-oligomerization to inhibit ATG14 dissociation, which in turn prevents VAMP8 from binding to STX17-SNAP29. Our results demonstrate that RUNDC1 is a negative regulator of autophagy that restricts autophagosome fusion with lysosomes and is crucial for zebrafish survival in nutrient-deficient conditions. Here, we summarize our findings and discuss their implications for our understanding of autophagy regulation.

Keywords: ATG14-STX17-SNAP29; RUNDC1; autophagosomes; autophagy; lysosomes; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes* / metabolism
  • Autophagy* / physiology
  • Lysosomes / metabolism
  • Membrane Fusion / physiology
  • SNARE Proteins / metabolism
  • Transcription Factors / metabolism
  • Zebrafish / metabolism

Substances

  • Transcription Factors
  • SNARE Proteins

Grants and funding

This work was supported by the National Natural Science Foundation of China (32000523 to RZ, 82273970 and 32070726 to JFT, 32270768 to CFZ), International Science and Technology Cooperation Project of Hubei Province (2022EHB038 to CFZ), Wuhan Science and Technology Project (2022020801020272 to CFZ, 2023020201020376 to RZ) and Innovation Group Project of Hubei Province (2023AFA026). VT was supported by the Enhanced Consumables Fund and Research Startup Fund from the School of Life Sciences (University of Westminster).