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

Abstract

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 positive 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) 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.

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Cite

BibTeX RIS

BibTeX

@article{yin2026crispr,
  title = {{CRISPR screening identifies GNPTAB as a noncanonical STING activator driving cellular senescence}},
  author = {Jian Yin and Yizhou Gao and Yaobin Jing and Xiaoyu Jiang and Feibo Wang and Yusheng Cai and Ming-Heng Li and Tianling Cao and Min Wang and Yifang He and Hongkai Zhao and Sheng Zhang and Shuai Ma and Si Wang and Guang-Hui Liu and Weiqi Zhang and Jing Qu},
  journal = {Protein \& Cell},
  year = {2026},
  month = jul,
  doi = {10.1093/procel/pwag049},
  url = {https://doi.org/10.1093/procel/pwag049},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - CRISPR screening identifies GNPTAB as a noncanonical STING activator driving cellular senescence
AU  - Jian Yin
AU  - Yizhou Gao
AU  - Yaobin Jing
AU  - Xiaoyu Jiang
AU  - Feibo Wang
AU  - Yusheng Cai
AU  - Ming-Heng Li
AU  - Tianling Cao
AU  - Min Wang
AU  - Yifang He
AU  - Hongkai Zhao
AU  - Sheng Zhang
AU  - Shuai Ma
AU  - Si Wang
AU  - Guang-Hui Liu
AU  - Weiqi Zhang
AU  - Jing Qu
PY  - 2026
DA  - 2026/07/27
JO  - Protein & Cell
DO  - 10.1093/procel/pwag049
UR  - https://doi.org/10.1093/procel/pwag049
AB  - 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 positive 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) 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.
SN  - 1674-800X
SN  - 1674-8018
ER  -

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