Osawa, I. Y. A. | Search bioRxiv

bioRxiv2026

Contact-phagy remodels ER-mitochondria contact sites

Membrane contact sites between the endoplasmic reticulum (ER) and other organelles coordinate cellular organization, metabolism and stress responses, yet how these interfaces are selectively remodeled and removed remains poorly understood. Here we identify a selective autophagy pathway that targets defined ER-mitochondria contact-site (ERMCS) subdomains for turnover, a process we term Contact-phagy. The ER-resident chaperone SIGMAR1 forms a functional complex with the ER-phagy receptor CCPG1, and SIGMAR1-CCPG1 nanoclusters define ERMCS-associated sites of autophagy initiation. Contact-phagy is selectively engaged by metabolic and mitochondrial stress and promotes turnover of defined contact-site components without broadly affecting general ER-phagy, mitophagy or bulk autophagy. At these sites, SIGMAR1-CCPG1 function is coupled to mitochondrial fission: MFF promotes DRP1 recruitment to ERMCS, whereas loss of CCPG1 or SIGMAR1 causes abnormal persistence and clustering of DRP1 and MFF, accompanied by altered mitochondrial remodeling. Loss of CCPG1 further disrupts ER-mitochondria organization and mitochondrial function in pancreatic tissue, while pancreatic cancer cells depend on CCPG1 and SIGMAR1 for organelle integrity and bioenergetic capacity. Together, our findings establish Contact-phagy as a selective pathway for the turnover of defined organelle contact site subdomains and suggest a broader principle by which interorganelle interfaces are maintained.

cell biology↗

bioRxiv2026

DUSP12 regulates NAT10-mediated RNA acetylation to modulate DNA repair and therapeutic response in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer arising from hepatocytes, is an aggressive hepatic malignancy with limited therapeutic options and poor prognosis. Chemotherapy remains an important treatment for advanced disease, though the mechanisms influencing drug sensitivity remain elusive. This study investigates the role of dual-specificity phosphatase 12 (DUSP12) and its interaction with the nucleolar protein NAT10 in the hepatic cellular response to genotoxic stress. We demonstrate that doxorubicin (DX) induces superior cytotoxicity over cisplatin in hepatocellular carcinoma models, associated with a stronger DNA damage response (DDR), nucleolar stress, and delocalization of NAT10 from the nucleolus to the nucleoplasm, where it colocalized with DUSP12. Genetic ablation of DUSP12 sensitized cells to DX, increasing DNA damage markers (p53, p-p53(Ser15), {gamma}H2AX(Ser139)) and delaying the repair of DNA strand breaks. DUSP12 knockout also caused redistribution of nucleolar proteins NAT10 and TCOF1. Pharmacological inhibition of NAT10 in DUSP12-deficient cells further enhanced DX sensitivity, revealing a synthetic-lethal interaction. We identified a direct association between NAT10 and DUSP12s functional domains, with evidence indicating NAT10 is a DUSP12 substrate. Consequently, DUSP12 knockout elevated NAT10 phosphotyrosine levels and reduced ac4C RNA acetylation, indicating functional impairment of NAT10. Corroborating these findings, patient data showed frequent DUSP12 amplification in HCC, correlating with poor survival and enrichment in DDR and ribosome biogenesis pathways. Our results establish the DUSP12-NAT10-ac4C axis as a molecular link between the DDR and nucleolar stress, highlighting previously unrecognized therapeutic vulnerability in HCC.

cancer biology↗