Counteracting lysosome defects alleviates the cellular senescence of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare progeroid disorder, and approximately 90% of cases are caused by LMNA mutation that yields the lamin A/C variant progerin. Progerin is toxic, and its clearance and disruption have positive benefits on HGPS cells and mice and even HGPS patients. However, accelerating progerin clearance is still an unaddressed issue. Here, we report that primary cells from HGPS patients displayed lysosome defects and that counteracting lysosome defects via the activation of lysosome biogenesis promoted progerin clearance and accordingly alleviated cellular senescence in HGPS. We revealed that nucleus-localized progerin was expelled into the cytoplasm via nuclear envelope (NE) budding and degraded through autophagy in HGPS cells. Lysosome defects occurred in HGPS cells and impaired progerin clearance. Activating lysosome biogenesis via the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or the mTORC1 inhibitor Torin 1 promoted progerin clearance and accordingly mitigated DNA damage, cell cycle arrest, low proliferation ability and senescence-associated secretory phenotype (SASP) in HGPS cells. Overall, we propose that, in HGPS, lysosomes exhibit defects and that activating lysosome biogenesis can accelerate progerin clearance and alleviate cellular senescence. These findings highlight the anti-senescence roles of PKC activation and lysosome biogenesis and provide new insights for understanding and treating HGPS.