CRISPR screening identifies GNPTAB as a noncanonical STING activator driving cellular senescence

作者：Jian Yin, Yizhou Gao, Yaobin Jing, Jiang Xh, Feibo Wang, Y Cai, Ming-Heng Li, Tianling Cao, M Wang, Yifang He, Hongyun Zhao, Sheng Zhang, S W, Si Wang, Guang‐Hui Liu, Weiqi Zhang, Jing Qu · 发表于：Protein & Cell · 年份：2026 · DOI：10.1093/procel/pwag049 · 研究领域：interferon and immune responses、Telomeres, Telomerase, and Senescence、Cell death mechanisms and regulation

Cellular senescence is accompanied by profound lysosomal alterations, yet whether lysosome-associated factors actively drive aging remains unclear. 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 potent regulator of cellular senescence. Genetic ablation of GNPTAB attenuated senescence, whereas its overexpression accelerated senescence. This pro-senescent function occurred independently of GNPTAB's canonical enzymatic role. Instead, GNPTAB binds to the innate immune adaptor stimulator of interferon genes (STING) via a specific interface (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, nominating this interface as a potential target for mitigating age-related cellular dysfunction.