MYO1G Facilitates Caveolin 1-Mediated Endocytosis of the N-Terminal Fragments of Gasdermin E to Restrain Pyroptosis and Chemotherapy Efficacy.

UNLABELLED: The N-terminal fragments of gasdermin (GSDM-NT) form pores on the plasma membrane that initiate pyroptosis. However, the presence of GSDM-NT pores does not necessarily result in cell death, allowing some cells to survive GSDM-mediated pyroptosis. Understanding the regulators of response to the formation of GSDM-NT pores is crucial for revealing the strategies to harness the potential of pyroptosis for treating cancer. In this study, we found that myosin 1G (MYO1G) enabled cells to resist death driven by membrane rupture. Mechanistically, MYO1G tethered GSDME-NT pores to caveolin 1 (CAV1), thus facilitating CAV1-mediated endocytosis of pyroptotic pores. Pyroptosis triggered the transcriptional upregulation of MYO1G through stabilization of hypoxia-inducible factor 1α (HIF1α), which resulted from the release of intracellular α-ketoglutarate. Moreover, pharmacologic inhibition of MYO1G or cholesterol synthesis promoted pyroptosis, boosted antitumor immunity, and synergized with chemotherapy to eradicate tumors. Clinically, MYO1G was validated as an indicator of poor short-term response to cisplatin-based chemotherapy and unfavorable long-term survival in patients with nasopharyngeal carcinoma. Overall, these findings provide further understanding of a protective mechanism against pyroptosis and identify potential therapeutic targets for cancer treatment.

SIGNIFICANCE: MYO1G-facilitated endocytosis of gasdermin E pores protects cancer cells against pyroptotic death and contributes to cancer chemotherapy resistance, which provides potential biomarker and therapeutic strategies for cancer.