Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

Abstract

Sirtuins (Sirt1-Sirt7) are NAD + -dependent protein deacetylases/ ADP ribosyltransferases, which play decisive roles in chromatin silencing, cell cycle regulation, cellular differentiation, and metabolism. Different sirtuins control similar cellular processes, suggesting a coordinated mode of action but information about potential cross-regulatory interactions within the sirtuin family is still limited. Here, we demonstrate that Sirt1 requires autodeacetylation to efficiently deacetylate targets such as p53, H3K9, and H4K16. Sirt7 restricts Sirt1 activity by preventing Sirt1 autodeacetylation causing enhanced Sirt1 activity in Sirt7 −/− mice. Increased Sirt1 activity in Sirt7 −/− mice blocks PPARγ and adipocyte differentiation, thereby diminishing accumulation of white fat. Thus, reduction of Sirt1 activity restores adipogenesis in Sirt7 −/− adipocytes in vitro and in vivo. We disclosed a principle controlling Sirt1 activity and uncovered an unexpected complexity in the crosstalk between two different sirtuins. We propose that antagonistic interactions between Sirt1 and Sirt7 are pivotal in controlling the signaling network required for maintenance of adipose tissue.sirtuin | acetylation | adipogenesis T he seven sirtuins in mammals (Sirt1-Sirt7) are involved in the regulation of essential cellular processes. Sirtuins rapidly adjust the activity of chromatin, transcription factors, metabolic enzymes, and structural proteins to cellular needs by deacetylating a broad range of targets. The ability to sense metabolic alterations and various stressors enable sirtuins to adapt cellular homeostasis to varying conditions. It seems likely that this feature of sirtuins is crucial to prevent age-dependent pathologies and promote a healthy lifespan (1, 2).Sirt1 is the most widely studied mammalian sirtuin showing the highest homology to the founding member of the sirtuin family, the yeast silence information regulator, Sir2. Sirt1 deacetylates histones H3K9, H3K56, H4K16, and H1K26 as well as many nonhistone targets thereby contributing to the maintenance of metabolic homeostasis and genomic integrity (3, 4). Sirt1 was also identified as a critical component of lifespan extension in response to calorie restriction in several model organisms, although its exact contribution is still under debate (5). The functions of Sirt7 have attracted less attention compared with Sirt1.

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

“…We have previously reported that Sirt7 interacts with and inhibits the Sirt1-mediated repression of PPARγ gene expression in adipocytes [19]. In contrast, Sirt7 promotes Sirt1 binding to rDNA together with DNA methyltransferase 1 (DNMT1) for induction of heterochromatin formation [21].…”

“…Since Sirt1 positively regulates Suv39h1 activity [20] and Sirt1 becomes autodeacetylated at K230 and hyperactive in Sirt7 deficient cells [19], we speculated that hyperactivation of Sirt1 plays the decisive role for increased Suv39h1 activity in Sirt7 depleted cells. To corroborate this assumption, we expressed different combination of Sirt1, Sirt7 and Suv39h1 in HEK293T cells and monitored H3K9me3 levels.…”

“…We found that Sirt1 together with Suv39h1 increased Suv39h1-dependent H3K9 methylation while addition of Sirt7 prevented this increase (Figure 3(A)). Since we previously attributed Sirt1 hyperactivity in Sirt7-deficient adipocytes to Sirt1 K230 autodeacetylation [19], we assumed that deacetylated Sirt1 might acquire a higher affinity to Suv39h1 and thereby more efficient Suv39h1 activation. Transfection of Sirt1 acetylation (Sirt1 K230Q) and deacetylation (K230R) mimicking mutants, and wildtype Sirt1 in HEK293T cells validated this assumption.…”

“…Sirt1 expression and activity are regulated at the transcription level, via mRNA stability and by several posttranslational modifications of the Sirt1 protein [16–18]. Recently, activation of Sirt1 by autodeacetylation at the lysine residue K230 was also documented [19], which is negatively regulated by another member of the sirtuin family, Sirt7. Absence of Sirt7 leads to hyperactive, deacetylated Sirt1 causing lipodystrophy in Sirt7 knockout mice due to repression of the PPARγ gene [19].…”

“…Recently, activation of Sirt1 by autodeacetylation at the lysine residue K230 was also documented [19], which is negatively regulated by another member of the sirtuin family, Sirt7. Absence of Sirt7 leads to hyperactive, deacetylated Sirt1 causing lipodystrophy in Sirt7 knockout mice due to repression of the PPARγ gene [19]. …”