AlaRS-mediated lactylation shields PARP1 from ubiquitination to promote HNSCC progression
Zhang, J.; Meng, X.; Qin, Q.; Zhou, Q.; Lu, Y.; Qin, R.; Yan, Y.; Liu, C.; Zhang, S.; Luo, X.; Liu, G.; Bian, Y.; Zhou, Z.-W.; Zhou, J.-C.; Gao, J.; Wei, L.; Ma, B.; Schimmel, P.; Sun, L.
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Abstract textMetabolic reprogramming in solid tumors causes massive lactate accumulation, yet how this drives oncogenesis remains incompletely understood. Here, we identify alanyl-tRNA synthetase (AlaRS) as a cellular lactyltransferase that promotes head and neck squamous cell carcinoma (HNSCC) progression. AlaRS directly catalyzes site-specific lactylation of the DNA repair protein PARP1 at lysines K249 and K667. Crucially, we uncover a competitive post-translational crosstalk wherein this lactylation directly antagonizes PARP1 ubiquitination. This "lactyl-shield" prevents proteasomal degradation, hyper-stabilizing the PARP1-Mortalin complex and sustaining tumor proliferation via p53/p21 dysregulation. To therapeutically exploit this mechanism, we identified chelerythrine (CHE) as a potent, selective inhibitor that directly binds the AlaRS catalytic center. CHE abrogates AlaRS lactyltransferase activity, destabilizes PARP1, and robustly suppresses HNSCC xenograft growth in vivo. These findings establish a novel metabolic-post-translational axis linking lactate accumulation to oncoprotein stabilization, providing a blueprint for targeting tRNA synthetase moonlighting functions in cancer.
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