SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1

By Fan Lan, José M. Cacicedo, N. Ruderman, Y. Ido. Journal of Biological Chemistry, 2008

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SIRT1, a histone/protein deacetylase, and AMP-activated protein kinase (AMPK) are key enzymes responsible for longevity and energy homeostasis. We examined whether a mechanistic connection exists between these molecules that involves the major AMPK kinase LKB1. Initial studies demonstrated that LKB1 is acetylated in cultured (HEK293T) cells, mouse white adipose tissue, and rat liver. In the 293T cells, SIRT1 overexpression diminished lysine acetylation of LKB1 and concurrently increased its activity, cytoplasmic/nuclear ratio, and association with the LKB1 activator STRAD. In contrast, short hairpin RNA for SIRT1, where studied, had opposite effects on these parameters. Mass spectrometric analysis established that acetylation of LKB1 occurs on multiple, but specific, lysine residues; however, only mutation of lysine 48 to arginine, which mimics deacetylation, reproduced all of the effects of activated SIRT1. SIRT1 also affected downstream targets of LKB1. Thus its overexpression increased AMPK and acetyl-CoA carboxylase phosphorylation, and conversely, RNA interference-mediated SIRT1 knockdown reduced AMPK phosphorylation and that of another LKB1 target MARK1. Consistent with the results in cultured cells, total LKB1 lysine acetylation was decreased by 60% in the liver of 48-h starved rats compared with starved-refed rats, and this was associated with modest but significant increases in both LKB1 and AMPK activities. These results suggest that LKB1 deacetylation is regulated by SIRT1 and that this in turn influences its intracellular localization, association with STRAD, kinase activity, and ability to activate AMPK.

Subfields: Geriatrics and Gerontology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/49401cd8e948ac54c570b501113370651436756c

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Citations in the corpus

Autophagy and the integrated stress response (2010, positive): “AMPK can also indirectly stimulate Sirt1 activation by the reduction of nicotinamide (NAM) and an increase in NAD+ that may be catalyzed by NAM phosphoribosyltransferase upregulation, thus completing the feed forward circuitry (Lan et al., 2008;Ruderman et al., 2010).”
SIRT1 and other sirtuins in Metabolism (2013, background): “Reciprocally SIRT1 activates AMPK by deacetylating LKB1 [80].”
AMPK, insulin resistance, and the metabolic syndrome. (2013, neutral): “SIRT1 can activate AMPK by deacetylating the upstream kinase LKB1, which promotes LKB1 translocation from the nucleus to the cytosol, where it is activated and in turn phosphorylates and activates AMPK (86–88).”
AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol (2009, background): “(27) reported that the activity of liver kinase B (LKB)-1, one of the AMPK kinases that is important for AMPK activity, is activated by resveratrol in a Sirt1dependent manner.”
Regulation of SIRT1 and Its Roles in Inflammation (2022, background): “SIRT1-mediated deacetylation Abbreviations: SIRT1, Silent information regulator sirtuin 1; SIRTs, Sirtuins; HDACIII Histone deacetylase III; FOXO1/3/4, Forkhead-box transcription factor 1/3/4; HSF1, Heat shock factor 1; HIF-1a, Hypoxia-inducible factor 1 alpha; NF-kB, Nuclear factor-kappa B; PPARa/g”
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “Alternatively, resveratrol may first activate SIRT1 in vivo, leading to AMPK activation via deacetylation and activation of the AMPK kinase LKB1 (Hou et al., 2008; Ivanov et al., 2008; Lan et al., 2008).”
Sirt1 and the Mitochondria (2016, background): “That Sirt1 may act upstream of AMPK has support in a previous report, which showed that Sirt1 could potentially deacetylate and activate the major AMPK activating kinase, Serine/threonine kinase 11 (STK11) (or liver kinase B1, LKB1) (Lan et al., 2008).”
AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan (2011, background): “Conversely, SIRT1 can stimulate the activity of LKB1, which subsequently activates AMPK [51].”