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Using proximity labeling by turboID (biotin ligase) fused with ACSS2 combined with LC-MS for identification of the proteins associated with ACSS2 in oncogene RAS activation induced senescent human IMR90 cell

ABSTRACT: Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological impacts of senescent cells on tissue microenvironments and contributes to ageing-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-coA from acetate and epigenetically regulates gene expression mostly through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. We used proximity labeling by turboID combined with LC-MS, identified PAICS, a key enzyme for purine metabolism which interacts with ACSS2. ACSS2 facilitates the acetylation of PAICS and promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA damage repair, which results in cytoplasmic chromatin fragment (CCF) accumulation and SASP.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Yang Li

LAB HEAD: Pingyu Liu

PROVIDER: PXD048937 | Pride | 2025-02-13

REPOSITORIES: pride

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	ACSS2-1.raw	Raw
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	ACSS2-3.raw	Raw
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Similar Datasets

Using the HA tagged PAICS immunoprecipitation combined with LC-MS for identification of the acetylation sites of PAICS protein in senescent human IMR90 cells at day 10 post oncogene RAS activation

Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological impacts of senescent cells on tissue microenvironments and contributes to ageing-associated disease progression. We used proximity labeling by turboID combined with LC-MS and identified PAICS, a key enzyme for purine metabolism which interacts with ACSS2. PAICS can be acetylated and the acetylation promotes autophagy-mediated degradation to limit purine metabolism and reduces dNTP pools for DNA damage repair, which results in cytoplasmic chromatin fragment (CCF) accumulation and SASP.

2025-02-13 | PXD048965 | Pride

Using proximity labeling by turboID (biotin ligase) fused with PAICS combined with LC-MS for identification of the acetyltransferase associated with PAICS in oncogene RAS activation induced senescent human IMR90 cell

Project description:We performed proximity labeling by turboID combined with LC-MS and identified PCAF which interacts with PAICS. Moreover, PCAF promotes the acetylation of PAICS and decreases the protein stability of PAICS. Here, we identify the specific acetyltransferase PCAF that may be involved in the acetylation modification of PAICS using LC-MS.

2025-02-13 | PXD054616 | Pride

ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological effects of senescent cell on tissue microenvironment and contributes to aging-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-CoA from acetate and epigenetically regulates gene expression through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. Here we show that ACSS2 drives SASP by promoting PAlCS acetylation to restrain purine metabolism. Genetic and pharmacological inhibition, as well as deletion of Acss2 in mice blunts SASP gene expression and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts and promotes acetylation of PAlCS, a key enzyme for purine metabolism. The acetylation of PAlCS promotes autophagy-mediated degradation of PAlCS to limit purine metabolism and reduces dNTP pools for DNA repair, which exacerbates cytoplasmic chromatin fragment (CCF) accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyI-CoA generation to purine metabolism through PAlCS acetylation that dictates the functionality of SASP, and identify ACSS2 as a potential senomorphic target for healthy aging and to prevent senescence-associated diseases.

2025-02-10 | GSE275173 | GEO

ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological effects of senescent cell on tissue microenvironment and contributes to aging-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-CoA from acetate and epigenetically regulates gene expression through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. Here we show that ACSS2 drives SASP by promoting PAlCS acetylation to restrain purine metabolism. Genetic and pharmacological inhibition, as well as deletion of Acss2 in mice blunts SASP gene expression and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts and promotes acetylation of PAlCS, a key enzyme for purine metabolism. The acetylation of PAlCS promotes autophagy-mediated degradation of PAlCS to limit purine metabolism and reduces dNTP pools for DNA repair, which exacerbates cytoplasmic chromatin fragment (CCF) accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAlCS acetylation that dictates the functionality of SASP, and identify ACSS2 as a potential senomorphic target for healthy aging and to prevent senescence-associated diseases.

2025-02-10 | GSE274295 | GEO

ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

Project description:ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

| PRJNA1149736 | ENA

ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

Project description:ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

| PRJNA1145898 | ENA

ASB11 controls purinosome formation through PAICS ubiquitination

Project description:Purine act as building block for DNA and RNA, provide cellular energy and signaling, and can generate cofactors such as NADH and coenzyme A. Purine de novo synthesis pathway begins with amino acids, ribose 5-phosphate, CO2 and NH3 with 6 enzymes and 10 enzymatic steps to convert PRPP to IMP. In previous study, under purine-depleted or other stimuli the six enzymes will form dynamic and reversible complex called purinosome to enhance the pathway flux. However, the mechanism of purinosome formation is unknown. Phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in the step7 and 8 of purine biosynthesis. In our lab, we used interactome and ubiquiylome to identify PAICS, which is a substrate of ASB11. ASB11 is a substrate adaptor of cullin 5 ubiquitin ligase complex and is able to bind PAICS for ubiquitination. Here, we found that ASB11 could increase purinosome formation without any stimuli. This effect depends on ASB11 E3 function, which can ubiquitinate PAICS on K74 site. We generate K74R mutation of PAICS so that ASB11 couldn’t ubiquitinate it. Interestingly, this mutant reduces the formation of purinosomes under purine-depleted and other stressed conditions. After further research, we found ASB11 expression level will increase under some specific conditions. Moreover, we analyzed TCGA database and found that the expression of ASB11 in melanoma cell is higher than normal cell. Consistent with our finding, melanoma cell has partially formed purinosome under basal condition because of the higher expression of ASB11. We guess that ASB11 may plays an important role in cancer cell.

2023-10-06 | PXD025298 | Pride

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [ChIP-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and directchum regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Genome-wide examination of histone H3 and H4 acetylation, as well as ACSS2 binding, in undifferentiated CAD cells and differentiated CAD neurons; background adjusted by H3 ChIP or Input.

2017-05-01 | E-GEOD-76850 | biostudies-arrayexpress

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [RNA-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).

2017-05-01 | E-GEOD-76853 | biostudies-arrayexpress

The Menin–Bach2 axis is critical for regulating CD4 T cell senescence and homeostasis

Project description:Although CD4 T cell senescence plays an important role in immunosenescence, the mechanisms remain unclear. We found that T cell-specific Menin deficiency results in the premature senescence of CD4 T cells, accompanied by the senescence-associated secretory phenotype (SASP) after antigenic stimulation. TH1 and TH2 differentiation was dysregulated in Menin-knockout CD4 T cells. Bach2, which regulates SASP and TH differentiation, was identified as a Menin target. Menin binds to the Bach2 locus, and controls its expression through maintenance of histone acetylation. These findings reveal a critical role of the Menin-Bach2 pathway in regulating CD4 T cell senescence and homeostasis, thus indicating the involvement of this pathway in the inhibition of age-associated development of inflammatory diseases, which are induced by immunosenescence. Examination of transcriptional factor Menin binding and histone modefications in Menin WT and KO CD4 T cells

2014-03-27 | E-GEOD-53831 | biostudies-arrayexpress

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