The N-end rule pathway regulates ER stress-induced clusterin release to the cytosol where it directs misfolded proteins for degradation

Previous work suggests that cell stress induces release of the normally secreted chaperone clusterin (CLU) into the cytosol. We analyzed the localization of CLU in healthy and stressed cells, the mechanism of its cytosolic release, and its interactions with cytosolic misfolded proteins. Key results of this study are the following: (1) full-length CLU is released to the cytosol during stress, (2) the CLU N-terminal D1 residue is recognized by the N-end rule pathway and together with the enzyme ATE1 is essential for cytosolic release, (3) CLU can form stable complexes with cytosolic misfolded proteins and direct them to the proteasome and autophagosomes, and (4) cytosolic CLU protects cells from hypoxic stress and the cytosolic overexpression of an aggregation-prone protein. Collectively, the results suggest that enhanced cytosolic release of CLU is a stress response that can inhibit the toxicity of misfolded proteins and facilitate their targeted degradation via both autophagy and the proteasome. [Display omitted] •Full-length secretory clusterin (CLU) is released to the cytosol during ER stress•The N-terminal CLU D1 residue and the enzyme ATE1 are required for CLU release to the cytosol•CLU can direct cytosolic misfolded proteins to the proteasome and autophagosomes•Cytosolic CLU can protect cells from stresses associated with cytosolic misfolded proteins Satapathy et al. show that stresses induce release of full-length secretory clusterin (CLU) from the ER/Golgi to the cytosol. The N-terminal CLU D1 residue and ATE1 expression are required for release. To protect cells during stresses, CLU complexes with misfolded proteins in the cytosol and directs them to degradation pathways.