The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer

J Clin Invest. 2024 Mar 21;134(10):e174587. [ PMID: 38512451 ]

Lactylation is a recently recognized posttranslational modification found on lysine residues of histones and many non-histone proteins. p300 was long assumed to deposit these marks, yet the proposed donor lactyl-coenzyme A sits at roughly one-thousandth the cellular concentration of acetyl-CoA, casting doubt on that model. Here the authors show that alanyl-tRNA synthetase 1 (AARS1) is a genuine lactyltransferase that ligates lactate onto proteins using ATP directly. Focusing on the Hippo pathway, they found that AARS1 detects intracellular lactate, relocates to the nucleus, and lactylates the YAP-TEAD complex to activate it. AARS1 is itself a Hippo target gene, forming a positive-feedback loop with YAP-TEAD that fuels gastric cancer cell growth. Clinically, AARS1 is upregulated in gastric cancer and its high expression forecasts poor prognosis. The work demonstrates AARS1 lactyltransferase activity in vitro and in vivo and reveals how the metabolite lactate becomes a proliferation signal.

Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion

Immunity. 2022 Jun 14;55(6):1067-1081.e8. [ PMID: 35659337 ]

How immunoregulatory B cells weaken antitumor immunity is incompletely defined. The authors identify a leucine-tRNA-synthetase-2 (LARS2)-expressing B cell subset (LARS B cells) with a TGF-beta1-dominant regulatory phenotype in mouse and human progressive colorectal cancer. These cells prefer leucine, show active mitochondrial aminoacyl-tRNA biosynthesis, and sit outside tertiary lymphoid structures; their presence tracks with colorectal hyperplasia and shorter patient survival. Feeding a leucine diet promotes LARS B cell generation, whereas deleting Lars2 or blocking leucine curbs immunoevasion. Mechanistically, LARS2 drives mitochondrial NAD+ regeneration and oxidative metabolism, engaging the NAD-dependent deacetylase SIRT1 to fix the regulatory identity of LARS B cells. The authors propose a leucine-dieting regimen to restrain LARS B cells as a safe, practical addition to colorectal cancer therapy.

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