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Nuclear GTPSCS functions as a lactyl-CoA ligase to promote histone lactylation and glioma progression

ABSTRACT: Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and hypoxia-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here, we report the identification of GTPSCS as a lactyl-CoA ligase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone H3 lysine 18 lactylation (H3K18la). This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit but also acetylation at the G2 subunit residue K73 (for the interaction between GTPSCS and p300). GTPSCS-p300-mediated histone H3K18la promotes glioma cell proliferation and tumor formation in mice. In addition, histone H3K18la is positively associated with glioma grade and poor prognosis in glioma patients. The LDHA-GTPSCS-lactyltransferase-histone Kla axis thus represents a signal-stimulated epigenetic pathway that mediates the downstream impact of the Warburg effect and hypoxia

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: He Huang

LAB HEAD: He Huang

PROVIDER: PXD037672 | Pride | 2024-12-04

REPOSITORIES: Pride

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			Action	DRS
	IPKla_Histone_SILAC_heavy192R.raw	Raw
	IPKla_Histone_SILAC_heavy192R_Lactyl__K_Sites.txt	Txt
	IPKla_Histone_SILAC_heavy192R_evidence.txt	Txt
	IPKla_Histone_SILAC_light192R.raw	Raw
	IPKla_Histone_SILAC_light192R_Lactyl__K_Sites.txt	Txt

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Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation

Project description:Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a lactyl-CoA synthetase in the nucleus using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation and radioresistance of gliomas. The GTPSCS represents the inaugural enzyme that can catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression patterns in glioma.

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Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a robust lactyl-CoA synthetase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation of glioma cells and facilitates tumor formation in mice. In addition, GTPSCS is upregulated in glioma and correlates with glioma malignancy, while histone H3K18la, and GDF15 levels are positively associated with glioma malignancy and poor prognosis in GBM patients. The GTPSCS-lactyltransferase-histone Kla axis thus represents an epigenetic pathway linking lactate metabolism with an oncogenic gene expression pattern in glioma.

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