
SIRT2 deacetylates ACSS2 at lysine 271 in response to nutrient stress, particularly amino acid deprivation, leading to ACSS2 ubiquitination and proteasomal degradation, which in turn suppresses de novo lipogenesis.


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De novo lipogenesis is associated with the development of human diseases such as cancer, diabetes, and obesity. At the core of lipogenesis lies acetyl coenzyme A (CoA), a metabolite that plays a crucial role in fatty acid synthesis. One of the pathways contributing to the production of cytosolic acetyl-CoA is mediated by acetyl-CoA synthetase 2 (ACSS2). Here, we reveal that when cells encounter nutrient stress, particularly a deficiency in amino acids, Sirtuin 2 (SIRT2) catalyzes the deacetylation of ACSS2 at the lysine residue K271. This results in K271 ubiquitination and subsequently proteasomal degradation of ACSS2. Substitution of K271 leads to decreased ubiquitination of ACSS2, increased ACSS2 protein level, and thus increased lipogenesis. Our study uncovers a mechanism that cells employ to efficiently manage lipogenesis during periods of nutrient stress.

### Competing Interest Statement

HL is a founder and consultant for Sedec Therapeutics

SIRT2-Mediated ACSS2 K271 Deacetylation Suppresses Lipogenesis Under Nutrient Stress

sirt2-mediated-deacetylation-of-acss2-at-k271-promotes-its-ubiquitination-and-degradation-suppressing-lipogenesis-under-nutrient-stress


SIRT2-Mediated Deacetylation of ACSS2 at K271 Promotes Its Ubiquitination and Degradation, Suppressing Lipogenesis Under Nutrient Stress
