1. Academic Validation
  2. Inhibition of class I PI3K enhances chaperone-mediated autophagy

Inhibition of class I PI3K enhances chaperone-mediated autophagy

  • J Cell Biol. 2020 Dec 7;219(12):e202001031. doi: 10.1083/jcb.202001031.
S Joseph Endicott 1 Zachary J Ziemba 2 Logan J Beckmann 2 Dennis N Boynton 2 Richard A Miller 1 3
Affiliations

Affiliations

  • 1 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.
  • 2 College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI.
  • 3 University of Michigan Geriatrics Center, Ann Arbor, MI.
Abstract

Chaperone-mediated Autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual Peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.

Figures
Products