Stress-Inducible Regulation of Heat Shock Factor 1 by the Deacetylase SIRT1

Abstract

Heat shock factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA–binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the heat shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

“…One factor known to modulate the HSR is the sirtuin family member SIRT1 (Liu et al, 2014; Raychaudhuri et al, 2014; Raynes et al, 2013; Westerheide, Anckar, Stevens, Sistonen, & Morimoto, 2009; Zelin & Freeman, 2015). SIRT1 is part of a family of conserved NAD + ‐dependent deacetylases and has broad roles in physiology and longevity (Haigis & Sinclair, 2010).…”

“…SIRT1 is part of a family of conserved NAD + ‐dependent deacetylases and has broad roles in physiology and longevity (Haigis & Sinclair, 2010). Increased expression of SIRT1 enhances the HSR through deacetylation of the DNA‐binding domain of HSF1, thereby prolonging its DNA‐binding competent state and allowing for increased transcription of hsp70 (Westerheide et al, 2009). SIRT1 is also essential for maintaining the proteome, as a SIRT1 deficiency results in defective protein quality control (Tomita et al, 2015).…”

Expanding Proteostasis by Membrane Trafficking Networks

“…For example, the APS has been shown to control the function of key proteostasis components (Westerheide et al 2009;Zeng et al 2009;Hutt et al 2010;Bouchareilh et al 2012) such as Hsp90 (Aoyagi and Archer 2005) and the central HSR transcription factor, heat shock factor 1 (HSF1) ( Fig. 1) (Westerheide et al 2009;Zeng et al 2009;Morimoto 2011). The APS also regulates protein degradation through its links to the UPS (Box 2) (Canettieri et al 2010;Du et al 2010;Alamdari et al 2012) as well as autophagy (Yi et al 2012).…”

“…1). For example, the APS has been shown to control the function of key proteostasis components (Westerheide et al 2009;Zeng et al 2009;Hutt et al 2010;Bouchareilh et al 2012) such as Hsp90 (Aoyagi and Archer 2005) and the central HSR transcription factor, heat shock factor 1 (HSF1) ( Fig. 1) (Westerheide et al 2009;Zeng et al 2009;Morimoto 2011).…”

Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

“…4.3 ). The importance of HAT/HDAC proteostatic activity is particularly evident not only in their impact in modulating posttranslationally the activity of many APL client proteins comprising the acetylome, but almost all PN components, including the core chaperones (Hsp90 [ 239 ], Hsp70 [ 240 ], Hsp40 [ 241 ], BiP [ 242 , 243 ]), the HSR transcription factor HSF1 [ 244 ], degradation processes (by directly competing for Lys ubiquitination [ 245 ]), and membrane traffi cking components including the assembly of microtubule and actin cytoskeletal polymers responsible for positioning and directing traffi c through both the exocytic and endocytic pathways [ 246 , 247 ]. Thus, HDACs globally impact proteostasis pathways by subtly modulating the thermodynamics and kinetics of the Q-state cloud biology in the context of the HDAC- Fig.…”