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

ABSTRACT: Cellular senescence is characterized 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 identify GNPTAB, an enzyme for lysosomal hydrolase targeting, as a potent regulator of senescence. Genetic ablation of GNPTAB attenuated senescence, while its overexpression accelerated aging. Notably, this pro-senescent function was independent of GNPTAB’s canonical enzymatic role. Mechanistically, GNPTAB binds to the innate immune adaptor STING via a specific interface (E1119), triggering downstream TBK1 activation and inflammatory gene expression. A STING-binding-deficient GNPTAB mutant (E1119A) retained enzymatic function but failed to induce senescence, and STING depletion abolished GNPTAB-driven senescence. Our work defines a non-canonical, lysosome-to-immune signaling pathway wherein GNPTAB acts as a direct STING activator, nominating this interface as a candidate target for mitigating age-related cellular dysfunction.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jing Qu

PROVIDER: PXD073027 | iProX | Sun Jan 11 00:00:00 GMT 2026

REPOSITORIES: iProX

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