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PACSIN1 is indispensable for amphisome-lysosome fusion during basal autophagy and subsets of selective autophagy

Journal PLoS Genet. 18(6):e1010264 (2022)
Title PACSIN1 is indispensable for amphisome-lysosome fusion during basal autophagy and subsets of selective autophagy
Laboratory Laboratory of Intracellular Membrane Dynamics〈Prof. YOSHIMORI Tamotsu〉
Abstract

Autophagy is an indispensable process that degrades cytoplasmic materials to maintain cellular homeostasis. During autophagy, double-membrane autophagosomes surround cytoplasmic materials and either fuse with endosomes (called amphisomes) and then lysosomes, or directly fuse with lysosomes, in both cases generating autolysosomes that degrade their contents by lysosomal hydrolases. However, it remains unclear if there are specific mechanisms and/or conditions which distinguish these alternate routes. Here, we identified PACSIN1 as a novel autophagy regulator. PACSIN1 deletion markedly decreased autophagic activity under basal nutrient-rich conditions but not starvation conditions, and led to amphisome accumulation as demonstrated by electron microscopic and co-localization analysis, indicating inhibition of lysosome fusion. PACSIN1 interacted with SNAP29, an autophagic SNARE, and was required for proper assembly of the STX17 and YKT6 complexes. Moreover, PACSIN1 was required for lysophagy, aggrephagy but not mitophagy, suggesting cargo-specific fusion mechanisms. In C. elegans, deletion of sdpn-1, a homolog of PACSINs, inhibited basal autophagy and impaired clearance of aggregated protein, implying a conserved role of PACSIN1. Taken together, our results demonstrate the amphisome-lysosome fusion process is preferentially regulated in response to nutrient state and stress, and PACSIN1 is a key to specificity during autophagy.

Authors

Yukako Oe (1), Keita Kakuda (2), Shin-ichiro Yoshimura (3), Naohiro Hara (4), Junya Hasegawa (5), Seigo Terawaki (6), Yasuyoshi Kimura (2), Kensuke Ikenaka (2), Shiro Suetsugu (7, 8, 9), Hideki Mochizuki (2), Tamotsu Yoshimori (1, 4, 10), Shuhei Nakamura (1, 4, 11)

  1. Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
  2. Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan
  3. Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
  4. Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan
  5. Department of Biochemical Pathophysiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
  6. Department of Molecular and Genetic Medicine, Kawasaki Medical School, Okayama, Japan
  7. Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Japan
  8. Data Science Center, Nara Institute of Science and Technology, Ikoma, Japan
  9. Center for Digital Green-Innovation, Nara Institute of Science and Technology, Ikoma, Japan
  10. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan
  11. Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan
PubMed 35771772

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