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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

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. 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Yang Li

LAB HEAD: Pingyu Liu

PROVIDER: PXD048965 | Pride | 2025-02-13

REPOSITORIES: pride

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			Action	DRS
	Exploris04267-SKY-LPY-YL-2023095-HA-PIP1-TAR.raw	Raw
	Exploris04267-SKY-LPY-YL-2023095-HA-PIP1-protein.xlsx	Xlsx
	checksum.txt	Txt

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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

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. 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.

2025-02-13 | PXD048937 | 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.

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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.

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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

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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

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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

Identification of ubiquitin binding protein using TurboID analysis

Project description:Purines serve as the building blocks for DNA and RNA, confer cellular energy and signaling. Purines are generated by de novo synthesis pathway and salvage pathway. Under purine-depleted or other cellular stresses, enzymes in the purine de novo synthesis pathway form a dynamic and reversible condensate called purinosome, but the underlying mechanism of purinosome formation is unknown. In this thesis, we found that ASB11-based Cul5 E3 ligase promotes ubiquitination of PAICS, a purine de novo synthesis enzyme. This ubiquitination does not lead to PAICS degradation, but drives purinosome assembly. We provide evidence that purinosome assembly involves a liquid-liquid phase separation (LLPS) process and identify several ubiquitin binding proteins that may bind ubiquitinated PAICS through a multivalent mode to drive LLPS and purinosome assembly. Importantly, ASB11 is upregulated under the stresses that promote purinosome assembly, thus increasing the formation of ASB11/PAICS complex. Finally, we demonstrated that melanoma cells express a high level of ASB11 to confer a constitutive purinosome formation, which support their viability. In summary, our study identifies ASB11-mediated PAICS ubiquitination as a driving mechanism for purinosome assembly, the regulation of this mechanism under stressed conditions, and the importance of this regulation in cell viability.

2023-10-06 | PXD027946 | Pride

Identification of Ubiquitination site of PAICS by LC-MS/MS

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MLL1 is essential for the senescence-associated secretory phenotype [RNA-Seq]

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