bims-meprid 2024-06-02 papers

Issue of 2024‒06‒02
two papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

bioRxiv. 2024 May 14. pii: 2024.05.09.593421. [Epub ahead of print]

Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion.

Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.

T cell exhaustion is linked to persistent antigen exposure and perturbed activation events, correlating with poor disease prognosis. Tumor-mediated T cell exhaustion is well documented; however, how the nutrient-deprived tumor niche affects T cell receptor (TCR) activation is largely unclear. We show that methionine metabolism licenses optimal TCR signaling by regulating the protein arginine methylome, and limiting methionine availability during early TCR signaling promotes subsequent T cell exhaustion. We discovered a novel arginine methylation of a Ca 2+ -activated potassium transporter, KCa3.1, prevention of which results in increased Ca 2+ -mediated NFAT1 activation, NFAT1 promoter occupancy, and T cell exhaustion. Furthermore, methionine supplementation reduces nuclear NFAT1 in tumor-infiltrating T cells and augments their anti-tumor activity. These findings demonstrate metabolic regulation of T cell exhaustion determined during TCR engagement.

DOI: https://doi.org/10.1101/2024.05.09.593421

J Biol Chem. 2024 May 28. pii: S0021-9258(24)01919-7. [Epub ahead of print] 107418

ACLY alternative splicing correlates with cancer phenotypes.

Julianna G Supplee, Hayley C Affronti, Richard Duan, Rebekah C Brooks, Zachary E Stine, Phuong T T Nguyen, Laura V Pinheiro, Michael C Noji, Jack M Drummond, Kevin Huang, Kollin Schultz, Chi V Dang, Ronen Marmorstein, Kathryn E Wellen.

ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism and provides nucleocytosolic acetyl-CoA necessary for protein acetylation. ACLY has two major splice isoforms: the full-length canonical "long" isoform and an uncharacterized "short" isoform in which exon 14 is spliced out. Exon 14 encodes 10 amino acids within a disordered region of the protein and includes at least 1 site that is dynamically phosphorylated. Both isoforms are expressed in healthy tissues to varying degrees. Analysis of human transcriptomic data revealed that the Percent Spliced In (PSI) of exon 14, i.e., the proportion of long isoform, is increased in several cancers and correlated with poorer overall survival in a pan-cancer analysis, though not in individual tumor types, which prompted us to explore potential biochemical and functional differences between ACLY isoforms. Here, we show that there are no discernible differences in enzymatic activity or stability between isoforms or phosphomutants of ACLY in vitro. Similarly, both isoforms and phosphomutants were able to rescue ACLY functions, including fatty acid synthesis and bulk histone acetylation, when re-expressed in Acly knockout cells. Deletion of Acly exon 14 in mice did not overtly impact development or metabolic physiology, nor did it attenuate tumor burden in a genetic model of intestinal cancer. Notably, expression of epithelial splicing regulatory protein 1 (ESRP1) is highly correlated with ACLY PSI. We report that ACLY splicing is regulated by ESRP1. In turn, both ESRP1 expression and ACLY PSI are correlated with specific immune signatures in tumors. Despite these intriguing patterns of ACLY splicing in healthy and cancer tissues, functional differences between the isoforms remain elusive.

DOI: https://doi.org/10.1016/j.jbc.2024.107418