C. elegans granulins promote an age-associated decline in protein homeostasis via lysosomal protease inhibition

Victoria J. Butler, Wilian A. Cortopassi, Andrea R. Argouarch, M. Olivia Pierce, Mihir Vohra, Juan A. Oses-Prieto, Fuying Gao, Benjamin Caballero, Shreya Chand, William W. Seeley, Bruce L. Miller, Giovanni Coppola, Alma L. Burlingame, Kaveh Ashrafi, Ana Maria Cuervo, Matthew P. Jacobson, Aimee W. Kao

Research output: Contribution to journalArticlepeer-review

Abstract

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases (or cathepsins) are key contributors to maintenance of protein homeostasis with age. Here, we identify the cysteine-rich granulin peptides as a new class of regulators of lysosomal aspartyl protease activity. Granulins are produced in an age and stress-dependent manner through cleavage of the neurodegenerative disease protein, progranulin. Once liberated, granulins selectively interact with the aspartyl protease ASP-3/cathepsin D to impair enzymatic activity. Consequently, protein homeostasis and lysosome function is disrupted, prompting cells to activate a compensatory transcriptional program. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Nov 17 2018

Keywords

  • C. elegans
  • cathepsin
  • granulin
  • lysosome
  • neurodegeneration
  • progranulin
  • protease
  • proteostasis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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