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Through a focused CRISPR\/Cas9 screen in human mesenchymal progenitor cells (hMPCs), we identified N-acetylglucosamine-1-phosphotransferase subunits alpha and beta (GNPTAB), an enzyme responsible for lysosomal hydrolase targeting, as a positive regulator of cellular senescence. Genetic ablation of GNPTAB attenuated senescence, whereas its overexpression accelerated senescence. This pro-senescent function occurred independently of GNPTAB\u2019s canonical enzymatic role. Instead, GNPTAB binds to the innate immune adaptor stimulator of interferon genes (STING) through an interface involving the critical residue E1119, leading to activation of STING and its downstream TANK-binding kinase 1 (TBK1), as well as pro-inflammatory gene expression. A STING-binding-deficient GNPTAB mutant (E1119A) preserved canonical lysosomal functions but failed to induce senescence, while STING depletion abolished GNPTAB-driven senescence. Together, these findings uncover a new signaling pathway wherein GNPTAB engages STING to facilitate its activation, suggesting that the GNPTAB-STING interaction interface may serve as a potential therapeutic target for ameliorating age-related cellular dysfunction.<\/jats:p>","DOI":"10.1093\/procel\/pwag049","type":"journal-article","created":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T11:31:11Z","timestamp":1785065471000},"source":"Crossref","is-referenced-by-count":0,"title":["CRISPR screening identifies GNPTAB as a noncanonical STING activator driving cellular senescence"],"prefix":"10.1093","author":[{"given":"Jian","family":"Yin","sequence":"first","affiliation":[{"name":"State Key Laboratory of Organ Regeneration and Reconstruction, Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing 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