insight - Biochemistry - # Regulation of acetyl-CoA synthetase 2 (ACSS2) by SIRT2-mediated deacetylation under nutrient stress

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

Q: How might the SIRT2-ACSS2 regulatory axis be exploited for therapeutic interventions in metabolic disorders associated with dysregulated lipogenesis, such as obesity and non-alcoholic fatty liver disease?

The SIRT2-ACSS2 regulatory axis presents a promising target for therapeutic interventions in metabolic disorders characterized by dysregulated lipogenesis. By understanding the mechanism through which SIRT2 deacetylates ACSS2, leading to its ubiquitination and subsequent degradation under conditions of nutrient stress, novel therapeutic strategies can be developed. One approach could involve the development of small molecule inhibitors or activators targeting SIRT2 to modulate its deacetylation activity on ACSS2. By inhibiting SIRT2, the stability of ACSS2 could be increased, leading to enhanced lipogenesis, which could be beneficial in conditions where lipid synthesis is impaired, such as in certain types of cancer where lipid metabolism is dysregulated. On the other hand, activating SIRT2 to promote the deacetylation and degradation of ACSS2 could be beneficial in conditions like obesity and non-alcoholic fatty liver disease, where excessive lipogenesis contributes to disease progression. Furthermore, targeting the specific acetylation site on ACSS2, such as K271, could also be explored for therapeutic interventions. Developing molecules that mimic the acetylated state of ACSS2 at K271, thereby preventing its deacetylation by SIRT2, could potentially stabilize ACSS2 and promote lipogenesis in conditions where enhanced lipid synthesis is beneficial. Conversely, molecules that enhance the deacetylation of ACSS2 at K271 by SIRT2 could be utilized to reduce lipogenesis in conditions where excessive fat accumulation is detrimental.

Q: How might the temporal and spatial coordination of these deacetylases contribute to the fine-tuning of lipogenesis under diverse physiological conditions?

The temporal and spatial coordination of different sirtuins, such as SIRT1 and SIRT2, in regulating ACSS2 activity and acetylation plays a crucial role in fine-tuning lipogenesis under diverse physiological conditions. SIRT1 and SIRT2 exhibit distinct substrate specificities and cellular localization, allowing for precise control over metabolic pathways like lipogenesis. In conditions where nutrient stress is prevalent, such as amino acid deprivation, SIRT2 is upregulated and deacetylates ACSS2 at K271, leading to its ubiquitination and degradation. This process results in the downregulation of lipogenesis, which is essential for cellular adaptation to nutrient scarcity. On the other hand, under normal physiological conditions, SIRT1 may deacetylate ACSS2 at a different site, such as K661, to activate its enzymatic activity and promote lipogenesis when nutrients are abundant. The coordinated action of SIRT1 and SIRT2 allows for the dynamic regulation of ACSS2 acetylation and activity based on the metabolic demands of the cell. This fine-tuning ensures that lipogenesis is appropriately modulated in response to changing nutrient availability, thereby maintaining metabolic homeostasis. The spatial distribution of these deacetylases within different cellular compartments further adds complexity to the regulation of lipogenesis, allowing for precise control over lipid metabolism in specific organelles or regions of the cell.

Q: What other metabolic pathways or enzymes might be regulated by SIRT2 in a similar manner to modulate cellular responses to nutrient stress?

In addition to ACSS2, SIRT2 may regulate other metabolic pathways and enzymes in a similar manner to modulate cellular responses to nutrient stress. One potential target could be ATP citrate lyase (ACLY), an enzyme involved in converting citrate to acetyl-CoA for fatty acid synthesis. SIRT2 may deacetylate ACLY under conditions of nutrient stress, leading to its destabilization and inhibition, thereby reducing the production of acetyl-CoA and subsequent lipogenesis. Moreover, enzymes involved in glucose metabolism, such as pyruvate dehydrogenase kinase (PDK) or phosphofructokinase (PFK), could also be targets of SIRT2-mediated deacetylation to modulate cellular responses to nutrient stress. By regulating the activity of these enzymes through acetylation, SIRT2 can influence the flux of glucose through glycolysis and the tricarboxylic acid (TCA) cycle, impacting energy production and lipid synthesis. Furthermore, SIRT2 may interact with key regulators of autophagy and mitophagy pathways, such as ATG proteins or PINK1/Parkin, to modulate cellular responses to nutrient stress. By deacetylating these proteins, SIRT2 could regulate the turnover of damaged organelles and cellular components, ensuring energy homeostasis and metabolic adaptation during periods of nutrient deprivation. Overall, SIRT2 likely exerts broad effects on cellular metabolism by modulating the acetylation status of key enzymes and regulators involved in nutrient sensing and energy production.

Conceitos essenciais

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.

Resumo

The study reveals a mechanism by which mammalian cells regulate de novo lipogenesis (DNL) in response to nutrient stress. The key findings are:

SIRT2, a class III deacetylase, deacetylates ACSS2 (acetyl-CoA synthetase 2) at lysine 271 under nutrient stress, particularly amino acid deprivation.
SIRT2-mediated deacetylation of ACSS2 at K271 exposes the site for ubiquitination, leading to proteasomal degradation of ACSS2.
The K271R mutant of ACSS2, which cannot be deacetylated by SIRT2, is more stable and promotes increased lipogenesis compared to wild-type ACSS2.
Inhibition of SIRT2 activity increases ACSS2 acetylation, decreases its ubiquitination and degradation, and enhances lipogenesis in cells expressing wild-type ACSS2, but not in cells expressing the K271R mutant.

The findings demonstrate that SIRT2-mediated deacetylation of ACSS2 at K271 is a key mechanism by which cells downregulate lipogenesis in response to nutrient stress, particularly amino acid limitation. This regulatory mechanism helps maintain cellular homeostasis by limiting lipogenesis when nutrients are scarce.

Customize Summary

Rewrite with AI

Generate Citations

Translate Source

To Another Language

Generate MindMap

from source content

Visit Source

biorxiv.org

Estatísticas

ACSS2 acetylation levels are increased upon SIRT2 knockdown under nutrient and amino acid stress conditions.
Endogenous ACSS2 protein levels are increased when SIRT2 is knocked down under nutrient and amino acid stress conditions.
The K271R mutant of ACSS2 exhibits enhanced stability compared to wild-type ACSS2 under amino acid limitation.

Citações

"SIRT2 deacetylates ACSS2 at a specific lysine residue, K271, in response to nutrient stress, particularly amino acid deprivation."
"SIRT2-mediated deacetylation of ACSS2 at K271 exposes the site for ubiquitination, ultimately marking ACSS2 for degradation."
"The K271R mutant of ACSS2, which cannot be deacetylated by SIRT2, is more stable and promotes increased lipogenesis compared to wild-type ACSS2."

Principais Insights Extraídos De

SIRT2-Mediated ACSS2 K271 Deacetylation Suppresses Lipogenesis Under Nutrient Stress

by Karim,R., Te... às www.biorxiv.org 02-29-2024

https://www.biorxiv.org/content/10.1101/2024.02.27.582293v1

Perguntas Mais Profundas

How might the SIRT2-ACSS2 regulatory axis be exploited for therapeutic interventions in metabolic disorders associated with dysregulated lipogenesis, such as obesity and non-alcoholic fatty liver disease?

The SIRT2-ACSS2 regulatory axis presents a promising target for therapeutic interventions in metabolic disorders characterized by dysregulated lipogenesis. By understanding the mechanism through which SIRT2 deacetylates ACSS2, leading to its ubiquitination and subsequent degradation under conditions of nutrient stress, novel therapeutic strategies can be developed. One approach could involve the development of small molecule inhibitors or activators targeting SIRT2 to modulate its deacetylation activity on ACSS2. By inhibiting SIRT2, the stability of ACSS2 could be increased, leading to enhanced lipogenesis, which could be beneficial in conditions where lipid synthesis is impaired, such as in certain types of cancer where lipid metabolism is dysregulated. On the other hand, activating SIRT2 to promote the deacetylation and degradation of ACSS2 could be beneficial in conditions like obesity and non-alcoholic fatty liver disease, where excessive lipogenesis contributes to disease progression.
Furthermore, targeting the specific acetylation site on ACSS2, such as K271, could also be explored for therapeutic interventions. Developing molecules that mimic the acetylated state of ACSS2 at K271, thereby preventing its deacetylation by SIRT2, could potentially stabilize ACSS2 and promote lipogenesis in conditions where enhanced lipid synthesis is beneficial. Conversely, molecules that enhance the deacetylation of ACSS2 at K271 by SIRT2 could be utilized to reduce lipogenesis in conditions where excessive fat accumulation is detrimental.

How might the temporal and spatial coordination of these deacetylases contribute to the fine-tuning of lipogenesis under diverse physiological conditions?

The temporal and spatial coordination of different sirtuins, such as SIRT1 and SIRT2, in regulating ACSS2 activity and acetylation plays a crucial role in fine-tuning lipogenesis under diverse physiological conditions. SIRT1 and SIRT2 exhibit distinct substrate specificities and cellular localization, allowing for precise control over metabolic pathways like lipogenesis.
In conditions where nutrient stress is prevalent, such as amino acid deprivation, SIRT2 is upregulated and deacetylates ACSS2 at K271, leading to its ubiquitination and degradation. This process results in the downregulation of lipogenesis, which is essential for cellular adaptation to nutrient scarcity. On the other hand, under normal physiological conditions, SIRT1 may deacetylate ACSS2 at a different site, such as K661, to activate its enzymatic activity and promote lipogenesis when nutrients are abundant.
The coordinated action of SIRT1 and SIRT2 allows for the dynamic regulation of ACSS2 acetylation and activity based on the metabolic demands of the cell. This fine-tuning ensures that lipogenesis is appropriately modulated in response to changing nutrient availability, thereby maintaining metabolic homeostasis. The spatial distribution of these deacetylases within different cellular compartments further adds complexity to the regulation of lipogenesis, allowing for precise control over lipid metabolism in specific organelles or regions of the cell.

What other metabolic pathways or enzymes might be regulated by SIRT2 in a similar manner to modulate cellular responses to nutrient stress?

In addition to ACSS2, SIRT2 may regulate other metabolic pathways and enzymes in a similar manner to modulate cellular responses to nutrient stress. One potential target could be ATP citrate lyase (ACLY), an enzyme involved in converting citrate to acetyl-CoA for fatty acid synthesis. SIRT2 may deacetylate ACLY under conditions of nutrient stress, leading to its destabilization and inhibition, thereby reducing the production of acetyl-CoA and subsequent lipogenesis.
Moreover, enzymes involved in glucose metabolism, such as pyruvate dehydrogenase kinase (PDK) or phosphofructokinase (PFK), could also be targets of SIRT2-mediated deacetylation to modulate cellular responses to nutrient stress. By regulating the activity of these enzymes through acetylation, SIRT2 can influence the flux of glucose through glycolysis and the tricarboxylic acid (TCA) cycle, impacting energy production and lipid synthesis.
Furthermore, SIRT2 may interact with key regulators of autophagy and mitophagy pathways, such as ATG proteins or PINK1/Parkin, to modulate cellular responses to nutrient stress. By deacetylating these proteins, SIRT2 could regulate the turnover of damaged organelles and cellular components, ensuring energy homeostasis and metabolic adaptation during periods of nutrient deprivation. Overall, SIRT2 likely exerts broad effects on cellular metabolism by modulating the acetylation status of key enzymes and regulators involved in nutrient sensing and energy production.