ZNRF2-mediated CD-M6PR degradation and lysosomal dysfunction aggravate cellular senescence and aging.

Lysosomal dysfunction is a hallmark of cellular senescence, yet the mechanisms governing lysosomal protein trafficking remain incompletely understood. Here, we show that CD-M6PR, a principal receptor for lysosomal enzyme transport, is markedly reduced in senescent fibroblasts and in aged mice and humans, and that its loss correlates with the severity of autolysosomal impairment. Mechanistically, the reduction of CD-M6PR in senescent cells mainly stems from the accelerated proteasome-mediated degradation. Utilizing structural predictions and experimental validation, we identified the E3 ubiquitin ligase ZNRF2 as a critical mediator of CD-M6PR's rapid degradation in senescent cells, facilitated by ZNRF2's elevated expression in these cells. We further link stress-induced mTORC1 activation to increased ZNRF2 expression, which in turn reduces CD-M6PR protein levels, impairs lysosomal enzyme trafficking, and compromises autolysosomal function, thereby exacerbating cellular senescence. Collectively, these data define a previously unrecognized mTORC1-ZNRF2-CD-M6PR axis and reveal a novel mechanism by which aberrant mTORC1 signaling promotes lysosomal dysfunction and senescence, with potential implications for therapeutic targeting of age-related pathologies.