Hsp70-Hsp110 chaperones deliver ubiquitin dependent and independent substrates to the 26S proteasome for proteolysis

Ganapathi Kandasamy, Claes Andréasson

J Cell Sci 2018 : jcs.210948 doi: 10.1242/jcs.210948 Published 5 March 2018


In protein quality control, proteotoxic misfolded proteins are recognized by molecular chaperones, ubiquitylated by dedicated quality-control ligases and delivered to 26S proteasome for degradation. The chaperone Hsp70 and its nucleotide exchange factor Hsp110 functions in the degradation of misfolded proteins by the ubiquitin-proteasome system via poorly understood mechanisms. Here we report that yeast Hsp110 (Sse1 and Sse2) functions in the degradation of Hsp70-associated ubiquitin conjugates at the post-ubiquitylation step and is required for the proteasomal degradation of ubiquitin-independent substrates. Hsp110 associates with the 19S regulatory particle of the 26S proteasome and interacts with Hsp70 to facilitate the delivery of Hsp70 substrates for proteasomal degradation. Using a highly defined ubiquitin-independent proteasome substrate we show that the mere introduction of a single Hsp70-binding site renders its degradation dependent on Hsp110. The findings define a dedicated and chaperone-dependent pathway for the efficient shuttling of cellular proteins to the proteasome with profound implications for understanding protein quality control and cellular stress management.

Key words: Protein degradation, Proteasome, Ubiquitin, Chaperone, Hsp70, Quality Control