HSP60 and HSP10 depletion provoke distinct biological responses
Hila Ben-David, Shani Gabbay, Sufa Sued-Hendrickson, Linor Cohen, Liron Levin, Nili Tickotsky Moskovitz, Ifat Abramovich, Shiran Dror, Yariv Brotman, Shai Kaluski-Kopach, Evelina Nikelshparg, Anat Ben-Zvi, Barak RotblatAbstract
The mitochondrial chaperone and co-chaperone HSP60/HSP10 (HSPD1/ HSPE1), the mammalian homologues of bacterial GroEL/GroES, form a barrel-and-lid complex to fold newly imported or misfolded mitochondrial proteins. Several lines of evidence suggest that HSPD1 and HSPE1 have diverged in function. HSPD1 and HSPE1 are found in different clusters in the ecological network of gene expression in cancer. MTHFD2 was demonstrated to be an endogenous client protein of HSPD1 that does not require HSPE1 for its folding. Newly imported proteins show differential dependencies on HSP60 and HSP10 in isolated yeast mitochondria. Finally, HSPE1 was found to regulate a mitochondrial GTPase and modulate amyloid fibril formation independently of HSPD1. Nevertheless, the extent to which HSPD1 and HSPE1 have diverged in function has not been explored. Here, we show divergent transcriptomic and metabolic responses to the depletion of HSP60 versus HSP10 in cancer cells, and divergent activation of the mitochondrial unfolded protein response across tissues in Caenorhabditis elegans. Importantly, responses to HSP10 depletion were not nested within those of HSP60 depletion. We speculate that HSPE1 has diverged from HSPD1 and may have additional new cellular functions.
This article is part of the Theo Murphy meeting issue ‘ProteostaSys: a systems view of proteostasis’.