Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis
Ruilong Liu. et al.
Cell Metab. 2024
In cancer, the Warburg effect is characterized by increased glycolysis for energy production, even in the presence of oxygen, leading to excessive lactate production. Recent studies suggest that lactate actively modulates tumor biology, including epigenetic modifications and gene expression. The key finding of this study is that nuclear GTPSCS functions as a lactyl-CoA synthetase, catalyzing the conversion of lactate to lactyl-CoA, which subsequently promotes histone lactylation (H3K18la). GTPSCS is upregulated in glioma and correlates with the malignancy of the tumor. Nuclear GTPSCS forms a complex with p300, facilitating the production of lactyl-CoA and H3K18la, but not succinyl-CoA or histone succinylation. The GTPSCS/p300/H3K18la axis regulates gene expression through the nuclear localization signal (NLS) of the GTPSCS G1 subunit and acetylation at the K73 residue of the G2 subunit, with GDF15 identified as the primary target of this pathway. Additionally, the GTPSCS/p300 complex promotes glioma development and radioresistance by modulating H3K18la and GDF15 levels. Thus, this study not only identifies GTPSCS as a key regulatory enzyme in the histone lactylation pathway but also elucidates its role in glioma progression. These findings offer new insights into the role of GTPSCS in glioma development and suggest its potential as a therapeutic target in cancer treatment.
DOI: 10.1016/j.cmet.2024.11.005
Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint![]()
Tsao, Hsiao Wei. et al.
Immunity. 2024
Immune checkpoint blockade (ICB) has significantly improved cancer immunotherapy, particularly in melanoma and non-small cell lung cancer. However, a substantial subset of patients fail to respond to ICB, highlighting the need to better understand the genetic and cellular factors that regulate ICB responses and mechanisms of resistance. Antigen presentation via MHC class I molecules is a key determinant in tumor immunotherapy responses, as it supports T cell-mediated immunity. However, MHC class I presentation can both activate and inhibit immune responses, with non-classical MHC class I molecules like HLA-E/Qa-1b mediating immune evasion by engaging inhibitory receptors such as NKG2A.In this study, the authors investigate the role of ERAP1, an aminopeptidase involved in trimming peptides for MHC class I presentation, in modulating ICB responses. They found that the loss of ERAP1 sensitizes tumor cells to immune checkpoint blockade, a process that is dependent on CD8+ T cells and NK cells. In vivo studies showed that ERAP1 deletion disrupted the NKG2A-HLA-E inhibitory checkpoint by altering the HLA-E peptidome, preventing NKG2A engagement. Moreover, both ERAP1 and ERAP2 exhibited functional redundancy in processing the VL9 peptide for HLA-E presentation, and the loss of both enzymes inactivated the NKG2A checkpoint in human cancer cells. These findings suggest that ERAP1 inhibition could serve as an effective strategy to disrupt the NKG2A-HLA-E axis and enhance the efficacy of cancer immunotherapy. ERAP1 deletion thus represents a novel approach to enhance tumor immunogenicity and overcome immune evasion mechanisms in cancer.DOI: 10.1016/j.immuni.2024.10.013
Editor & Reviewer: Congci Yu
