Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and <i>C. elegans</i>

• Main Authors: Minh Tu Nguyen, Milán Somogyvári, Csaba Sőti
• Format: Article
• Language: English
• Published: MDPI AG 2018-11-01
• Series: International Journal of Molecular Sciences
• Subjects: aging; <i>daf-21</i>; HDAC; stress; proteostasis; signaling; metabolism; epigenetics; <i>sir-2.1</i>
• Online Access: https://www.mdpi.com/1422-0067/19/11/3661

Sirtuin 1 (SIRT1) othologs are ubiquitous NAD⁺-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 &#8217;client&#8217; 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.