SIRT2-Mediated ACSS2 K271 Deacetylation Suppresses Lipogenesis Under Nutrient Stress
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Curated by eLife
eLife assessment
This useful study describes a role for acetylation in controlling the stability of acetyl-CoA synthetase 2, which converts acetate to acetyl-CoA for de novo lipid synthesis. While some aspects of the study are solid, the overall evidence supporting these findings is incomplete. Including additional critical controls for protein levels and stability and extending the findings to additional cell lines will strengthen the study. This work will be of interest to researchers studying lipid metabolism and related diseases.
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Abstract
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.
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eLife assessment
This useful study describes a role for acetylation in controlling the stability of acetyl-CoA synthetase 2, which converts acetate to acetyl-CoA for de novo lipid synthesis. While some aspects of the study are solid, the overall evidence supporting these findings is incomplete. Including additional critical controls for protein levels and stability and extending the findings to additional cell lines will strengthen the study. This work will be of interest to researchers studying lipid metabolism and related diseases.
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Reviewer #1 (Public Review):
Summary:
In this manuscript, the authors delineate the crucial role of the SIRT2-ACSS2 axis in ACSS2 degradation. They demonstrate that SIRT2 acts as an ACSS2 deacetylase specifically under nutrient stress conditions, notably during amino acid deficiency. The SIRT2-mediated deacetylation of ACSS2 at K271 consequently triggers its proteasomal degradation. Additionally, they illustrate that acetylation of ACSS2 at K271 enhances ACSS2 protein levels, thereby promoting De Novo lipogenesis.
Strengths:
The findings presented in this manuscript are clearly interesting.
Weaknesses:
Further support is required for the model put forward by the authors.
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Reviewer #2 (Public Review):
Summary:
Karim et al investigated the regulation of ACSS2 by SIRT2. The authors identified a previously undescribed acetylation that they then show is important for the regulation and stability of ACSS2 in cells. The authors show that ACSS2 ubiquitination and degradation by the proteasome is regulated by SIRT2-mediated deacetylation of ACSS2 and that stabilizing ACSS2 by blocking SIRT2 can alter lipid accumulation in adipocytes.
Strengths:
Identification of a novel acetylation site on ACSS2 that regulates its protein stability and that has consequences on its activity in adipocytes. Multiple standard approaches were used to manipulate the expression and function of SIRT2 and ACSS2 (i.e., overexpression, knockdown, inhibitors).
Weaknesses:
The authors do not show direct deacetylation of ACSS2 by SIRT2 in an …
Reviewer #2 (Public Review):
Summary:
Karim et al investigated the regulation of ACSS2 by SIRT2. The authors identified a previously undescribed acetylation that they then show is important for the regulation and stability of ACSS2 in cells. The authors show that ACSS2 ubiquitination and degradation by the proteasome is regulated by SIRT2-mediated deacetylation of ACSS2 and that stabilizing ACSS2 by blocking SIRT2 can alter lipid accumulation in adipocytes.
Strengths:
Identification of a novel acetylation site on ACSS2 that regulates its protein stability and that has consequences on its activity in adipocytes. Multiple standard approaches were used to manipulate the expression and function of SIRT2 and ACSS2 (i.e., overexpression, knockdown, inhibitors).
Weaknesses:
The authors do not show direct deacetylation of ACSS2 by SIRT2 in an in vitro biochemical assay.
It would have been nice to have included a bona-fide SIRT2 target as a control throughout the study.
Throughout the manuscript, normalizing the data to 1 and then comparing the fold-change using a t-test is not the best statistical approach in that situation since every normalized value for control is 1 with zero standard deviation. The authors should consider an alternative statistical approach.
Though not necessary, using 13C-acetate or D3-acetate tracing would be better for understanding the impact of acetylation on the activity of ACSS2 and its impact on lipogenesis.
Did the authors also consider investigating SIRT1 in their assays? SIRT1 activates ACSS2 while SIRT2 leads to degradation of ACSS2. They should at least discuss these seemingly opposing roles of SIRT1 and SIRT2 in the regulation of ACSS2 and acetate metabolism in more depth, particularly as it concerns situations (i.e., diseases, pathologies) where either SIRT1, SIRT2, or both sirtuins, are active. This would enhance the significance of the findings to the broader research community.
In Figure 3, the authors should consider immunoblotting for endogenous ACSS2 throughout the differentiation and lipogenesis study since the total ACSS2 levels is the crucial aspect to affecting acetate-dependent promotion of lipogenesis in adipocytes, and to confirm TM-dependent stabilization of ACSS2 in that assay.
Do the authors have any data proving the K271 mutants of ACSS2 are still functional? Or that K271 ACSS2 protein is folded correctly?
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Reviewer #3 (Public Review):
Summary:
The manuscript shows SIRT2 can regulate acetylation of ACSS2 at residue 271, acetylation of 271 protects ACSS2 from proteasomal degradation in a SIRT2-dependent manner. Lastly, authors show that ACSS2 acetylation at K271 promotes lipid accumulation.
Strengths:
The author provides solid data showing ACSS2 acetylation can be regulated by targeting SIRT2 and that SIRT2 regulates ACSS2 ubiquitination. They identify K271 as a site of acetylation and show this is a site when mutated alters SIRT2-mediated ubiquitination.
Weaknesses:
However, data for this manuscript seems preliminary as nearly all data is performed in one cell line, some of the conclusions are not well supported by data and the overall role of ACSS2 K271 acetylation is not well characterized.
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