Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and C. elegans

Abstract

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 Caenorhabditis elegans 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 hsp-90 gene silencing also induces SIR-2.1 protein depletion and proteasomal degradation in C. elegans. 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.

iTRAQ-Based Quantitative Proteomic Analysis Reveals Toxicity Mechanisms in Chlamys farreri Exposed to Okadaic Acid

“…In the present study, the expression of both HSPs and CYP450 genes increased with the OA exposure time, supporting their roles in stress response and detoxification process to OA. The time-dependent changes in genes to OA are also in line with the result of previous studies involving other environmental stresses (Liu et al, 2018;Nguyen et al, 2018;Nie et al, 2020;Zhang et al, 2020). We hypothesize that overexpression of the HSPs gene may counteract the proteins damaged by the ROS after OA exposure, while the enhanced synthesis of CYP450 may contribute to complete the biotransformation of OA.…”

Enhanced Healthspan in Caenorhabditis elegans Treated With Extracts From the Traditional Chinese Medicine Plants Cuscuta chinensis Lam. and Eucommia ulmoides Oliv.

“…Molecular chaperones were shown to be implicated in adaptive stress response and hormesis ( Lakshmi et al, 2020 ), and especially heat shock proteins and their chaperone-activities play a fundamental role in hormesis in C. elegans ( Zhao and Wang, 2012 ). Therefore, daf-21 ( hsp-90 ) was specifically selected due to its implication in pathogenic stress resistance ( JebaMercy et al, 2016 ; Balasubramaniam et al, 2019 ), in the stabilization of the ageing-relevant nutrient-sensor SIR-2.1 ( Nguyen et al, 2018 ) and the DAF-16-mediated lifespan regulation ( Somogyvári et al, 2018 ). Furthermore, in response to hormetic life- and healthspan prolonging treatments, the up-regulation of hsp-16.1 ( Yanase et al, 1999 ; Lin et al, 2019 ), hsp-16.2 ( Olsen et al, 2006 ; Hartwig et al, 2009 ), as well as hsp-70 and hsp-12.6 ( Pietsch et al, 2011 ) was described.…”

Healthspan Enhancement by Olive Polyphenols in C. elegans Wild Type and Parkinson’s Models

“…Interestingly, the sirtuin family, named after mammalian Sirtuin 1 (SIRT1), features a high number of sirtuin-orthologs in several organisms, such as SIR-2.1 in C. elegans. Recently, it has been demonstrated that HSP-90/Hsp90 modulates lifespan via SIR-2.1/SIRT1 in C. elegans and in mammalian cells [76].…”