| Summary: | Sirtuin 1 (SIRT1) othologs are ubiquitous NAD<sup>+</sup>-dependent deacetylases that act as nutrient sensors and modulate metabolism and stress responses in diverse organisms. Both mammalian SIRT1 and <i>Caenorhabditis elegans</i> SIR-2.1 have been implicated in dietary restriction, longevity, and healthspan. Hsp90 is an evolutionarily conserved molecular chaperone that stabilizes a plethora of signaling ’client’ proteins and regulates fundamental biological processes. Here we report that Hsp90 is required for conformational stabilization of SIRT1 and SIR-2.1. We find that inhibition of Hsp90 by geldanamycin (GA) induces the depletion of mammalian SIRT1 protein in a concentration and time dependent manner in COS-7 and HepG2 cells. In contrast to SIRT1, SIRT2 level remains unchanged by GA treatment, reflecting a specific Hsp90 SIRT1 interaction. Hsp90 inhibition leads to the destabilization and proteasomal degradation of SIRT1. Moreover, we observe a GA-sensitive physical interaction between SIRT1 and Hsp90 by immunoprecipitation. We also demonstrate that <i>hsp-90</i> gene silencing also induces SIR-2.1 protein depletion and proteasomal degradation in <i>C. elegans</i>. Our findings identify metazoan SIRT1 orthologs as Hsp90 clients and reveal a novel crosstalk between the proteostasis and nutrient signaling networks, which may have implications in various age related diseases.
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