Understanding the Function of Mammalian Sirtuins and Protein Lysine Acylation

Abstract

Protein lysine acetylation is an important posttranslational modification that regulates numerous biological processes. Targeting lysine acetylation regulatory factors, such as acetyltransferases, deacetylases, and acetyl-lysine recognition domains, has been shown to have potential for treating human diseases, including cancer and neurological diseases. Over the past decade, many other acyl-lysine modifications, such as succinylation, crotonylation, and long-chain fatty acylation, have also been investigated and shown to have interesting biological functions. Here, we provide an overview of the functions of different acyl-lysine modifications in mammals. We focus on lysine acetylation as it is well characterized, and principles learned from acetylation are useful for understanding the functions of other lysine acylations. We pay special attention to the sirtuins, given that the study of sirtuins has provided a great deal of information about the functions of lysine acylation. We emphasize the regulation of sirtuins to illustrate that their regulation enables cells to respond to various signals and stresses. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

NAD+-consuming enzymes in immune defense against viral infection

“…There are seven sirtuins, SIRT1-7, in humans. They regulate diverse functions, including transcription, genome stability, metabolism, and cell signaling via deacylating various substrate proteins [ 116 , 117 ]. Although the roles of sirtuins in viral infection have not been investigated extensively and the literature does not provide a unifying picture, some evidence points to a protective role of sirtuins in fighting infection.…”

Brain Signaling of Indispensable Amino Acid Deficiency

“…The mechanisms for this rapid recognition of IAAD involve an enzyme important in the initiation of new protein synthesis: General Control Nonderepressible 2 (GCN2) and its target, phosphorylated eIF2α can be seen in Figure 6 of [ 40 , 41 ] and has been the subject of many reviews. For example, in 2021 alone, see [ 42 , 43 , 44 , 45 ]. The mechanisms involve an accumulation of uncharged tRNA because the limiting IAA that is deficient in the plasma and brain cannot adequately charge its cognate tRNA.…”

Sirtuin Modulators in Cellular and Animal Models of Human Diseases

“…In humans, there are seven sirtuins (SIRT1-7), with different acyl group specificities and subcellular localizations. Through deacylation, sirtuins regulate a wide range of biological functions, such as cell proliferation, metabolism, transcription, apoptosis, and cell signaling (Avalos et al, 2005;Machado de Oliveira et al, 2012;Morris, 2013;Hu et al, 2014;Jing and Lin, 2015;Bheda et al, 2016;Blank et al, 2017;Cha et al, 2017;Kosciuk et al, 2019;Wang and Lin, 2021). Consequently, sirtuins have been linked to various diseases, including cancer, neurological, and cardiovascular diseases (Borradaile and Pickering, 2009;Haigis and Sinclair, 2010;Hu et al, 2014;Fujita and Yamashita, 2018).…”

“…All seven sirtuins use a similar mechanism to catalyze lysine deacylation (Avalos et al, 2005;Feldman et al, 2015;Wang and Lin, 2021). First, the amide group of the acyl lysine attacks C1 of the NAD + ribose and releases nicotinamide (Figure 1).…”

“…The deprotonated 2′-hydroxyl group attacks the C1′-Oalkylamidate intermediate, forming a 1′,2′-cyclic intermediate. The acyl group is transferred to the 2′-hydroxyl group and releases the deacylated lysine product and 2′-O-acyl ADP-ribose (Avalos et al, 2005;Feldman et al, 2015;Wang and Lin, 2021).…”