Unconventional Protein Secretion and Protein Quality Control

Abstract

To safeguard proteomic integrity, cells rely on the ubiquitin proteasome system to degrade aberrant polypeptides and autophagy to eliminate protein aggregates. However, it is unclear whether cells can remove defective proteins that escape degradation due to protein quality control (PQC) failure or proteasome dysfunction lest toxic protein aggregates be formed. Here we report a pathway termed Misfolding‐Associated Protein Secretion (MAPS), which utilizes the endoplasmic reticulum (ER)‐associated deubiquitinase USP19 to export aberrant cytosolic proteins that are inefficiently degraded by the proteasome. USP19 possesses both deubiquitinating and chaperone activity, allowing recruitment of misfolded proteins to the ER for deubiquitination, encapsulation into ER‐associated vesicles, and subsequent secretion. USP19 deficient cells are defective in growth after exposing to a proteasome inhibitor, suggesting a critical role in adaptation to proteasome dysfunction. Together, our findings delineate a novel PQC pathway that, unlike degradation‐based mechanism, promotes protein homeostasis by exporting misfolded proteins through an unconventional route.Support or Funding InformationThe research is funded by the intramural research program of NIDDK.