SIRT6 transcriptionally regulates global protein synthesis through transcription factor Sp1 independent of its deacetylase activity

Abstract

Global protein synthesis is emerging as an important player in the context of aging and age-related diseases. However, the intricate molecular networks that regulate protein synthesis are poorly understood. Here, we report that SIRT6, a nuclear-localized histone deacetylase represses global protein synthesis by transcriptionally regulating mTOR signalling via the transcription factor Sp1, independent of its deacetylase activity. Our results suggest that SIRT6 deficiency increases protein synthesis in mice. Further, multiple lines of in vitro evidence suggest that SIRT6 negatively regulates protein synthesis in a cell-autonomous fashion and independent of its catalytic activity. Mechanistically, SIRT6 binds to the zinc finger DNA binding domain of Sp1 and represses its activity. SIRT6 deficiency increased the occupancy of Sp1 at key mTOR signalling gene promoters resulting in enhanced expression of these genes and activation of the mTOR signalling pathway. Interestingly, inhibition of either mTOR or Sp1 abrogated the increased protein synthesis observed under SIRT6 deficient conditions. Moreover, pharmacological inhibition of mTOR restored cardiac function in muscle-specific SIRT6 knockout mice, which spontaneously develop cardiac hypertrophy. Overall, these findings have unravelled a new layer of regulation of global protein synthesis by SIRT6, which can be potentially targeted to combat aging-associated diseases like cardiac hypertrophy.

Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease

“…Lower levels of IGF-1 delayed the process of aging. Transgenic mice models that overexpressed the Sirt6 gene had low levels of IGF-1, slowing the aging process in mice ( Kanfi et al, 2012 ; Ravi et al, 2019 ). Thus, Sirt6 can be targeted for therapeutic interventions in aging and aging related diseases ( Khan R. I. et al, 2018 ).…”

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

“…Sirt6, a member of the mammalian sirtuin family, is a NAD + -dependent deacetylase that modifies the 9, 18 and 56 lysine residues of histone H3 (H3K9ac, H3K56ac and H3K18ac) [2,3] and the lysine residues of many other transcription factors [4][5][6]. These functions make Sirt6 an important epigenetic regulator of chromatin and nuclear signaling systems, involved in heterochromatin silencing and genome maintenance, differentiation regulation, tumor suppression, and regulation of glycolipid metabolism balance [7][8][9][10].…”

Measuring Protein Synthesis in Cultured Cells and Mouse Tissues Using the Non‐radioactive SUnSET Assay

“…For more examples of the use of the SUnSET assay, the reader is directed to prior reports (Goodman et al., 2011; Ravi et al., 2018; Ravi et al., 2019; Schmidt et al., 2009).…”

“…Nevertheless, protein synthesis levels are dynamic and can be altered by various environmental factors as well as cell‐intrinsic mechanisms (Roux & Topisirovic, 2012). In addition, and quite importantly, protein synthesis is dysregulated in a variety of conditions, including cancer, heart diseases, neurodegenerative diseases, muscle wasting, and inherited genetic disorders (Gordon, Kelleher, & Kimball, 2013; Le Quesne, Spriggs, Bushell, & Willis, 2010; Ravi et al., 2019; Scheper, van der Knaap, & Proud, 2007; Zeitz & Smyth, 2020). Studying the regulation and dysregulation of this process by tracking changes in protein synthesis is thus of interest to many researchers, which makes it important to have simple and efficient tools to monitor protein synthesis regularly under both in vitro and in vivo conditions.…”