The noncanonical role of the protease cathepsin D as a cofilin phosphatase

Cell Res. 2021 Jul;31(7):801-813. doi: 10.1038/s41422-020-00454-w. Epub 2021 Jan 29.

Abstract

Cathepsin D (cathD) is traditionally regarded as a lysosomal protease that degrades substrates in acidic compartments. Here we report cathD plays an unconventional role as a cofilin phosphatase orchestrating actin remodeling. In neutral pH environments, the cathD precursor directly dephosphorylates and activates the actin-severing protein cofilin independent of its proteolytic activity, whereas mature cathD degrades cofilin in acidic pH conditions. During development, cathD complements the canonical cofilin phosphatase slingshot and regulates the morphogenesis of actin-based structures. Moreover, suppression of cathD phosphatase activity leads to defective actin organization and cytokinesis failure. Our findings identify cathD as a dual-function molecule, whose functional switch is regulated by environmental pH and its maturation state, and reveal a novel regulatory role of cathD in actin-based cellular processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors*
  • Actins
  • Cathepsin D*
  • Cofilin 1
  • Peptide Hydrolases
  • Phosphoric Monoester Hydrolases

Substances

  • Actin Depolymerizing Factors
  • Actins
  • Cofilin 1
  • Phosphoric Monoester Hydrolases
  • Peptide Hydrolases
  • Cathepsin D