2. Academic Validation
  3. A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion

A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion

  • Sci Adv. 2023 Oct 13;9(41):eadh1134. doi: 10.1126/sciadv.adh1134.
Jie Li 1 2,  Gregory J Krause 3 4,  Qi Gui 1 2,  Susmita Kaushik 3 4,  Gergely Rona 1 2 5,  Qingyue Zhang 1 2,  Feng-Xia Liang 6,  Avantika Dhabaria 1 2 7,  Carlos Anerillas 8,  Jennifer L Martindale 8,  Nikita Vasilyev 1 2 5,  Manor Askenazi 1 9,  Beatrix Ueberheide 1 2 7,  Evgeny Nudler 1 2 5,  Myriam Gorospe 8,  Ana Maria Cuervo 3 4,  Michele Pagano 1 2 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 2 Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 3 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 4 Institute for Aging Research, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 5 Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 6 Microscopy Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 7 Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 8 Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
  • 9 Biomedical Hosting LLC, 33 Lewis Avenue, Arlington, MA 02474, USA.
PMID: 37831778 DOI: 10.1126/sciadv.adh1134
Abstract

Intracellular degradation of proteins and organelles by the autophagy-lysosome system is essential for cellular quality control and energy homeostasis. Besides degradation, endolysosomal organelles can fuse with the plasma membrane and contribute to unconventional secretion. Here, we identify a function for mammalian SKP1 in endolysosomes that is independent of its established role as an essential component of the family of SCF/CRL1 ubiquitin ligases. We found that, under nutrient-poor conditions, SKP1 is phosphorylated on Thr131, allowing its interaction with V1 subunits of the vacuolar ATPase (V-ATPase). This event, in turn, promotes V-ATPase assembly to acidify late endosomes and enhance endolysosomal degradation. Under nutrient-rich conditions, SUMOylation of phosphorylated SKP1 allows its binding to and dephosphorylation by the PPM1B Phosphatase. Dephosphorylated SKP1 interacts with SEC22B to promote unconventional secretion of the content of less acidified hybrid endosomal/autophagic compartments. Collectively, our study implicates SKP1 phosphorylation as a switch between Autophagy and unconventional secretion in a manner dependent on cellular nutrient status.

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