TOLLIP targets GSDME-NT-carrying endocytic vesicles for autophagy to regulate pyroptosis and chemotherapy efficacy

  • Nat Cell Biol. 2026 Apr;28(4):812-827. doi: 10.1038/s41556-026-01902-2.
Zhimin Xu  #  1  2  3 ,  Zhe Li  #  1  2  3 ,  Zhenji Deng  #  1  2  3 ,  Cong Ding  1 ,  Jiawei Wu  1 ,  Chuqing Zhang  1  2  3 ,  Hanmiao Wei  1  2  3 ,  Tingxiang He  1  2  3 ,  Liufen Long  1  2 ,  Linglong Tang  4  5  6 ,  Jun Ma  7  8  9 ,  Xiaoyu Liang  10  11  12
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2. Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4. State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 5. Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 6. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 7. State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 8. Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 9. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 10. State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 11. Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 12. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41803502 DOI: 10.1038/s41556-026-01902-2
Abstract

Whether Pyroptosis is controllable and reversible remains an enigma. Here we revealed that Autophagy could eliminate the pore-formed N terminus of GSDME (GSDME-NT) located on membranes at different locations, suppressing Pyroptosis. Crucially, GSDME-NT on the plasma membrane was eliminated through endocytic internalization, where GSDME-NT-laden vesicles were targeted and degraded as intact units. Specifically, GSDME-NT pores on the plasma membrane induced endocytosis, generating endocytosed but leaky vesicles carrying GSDME-NT. Leakage prevented acidification, necessitating further degradation through Autophagy. Upon endocytosis, GSDME-NT on the vesicle membrane was labelled with ubiquitin by calcium-activated E3 Ligase NEDD4L. These labelled vesicles were recognized by TOLLIP, guiding subsequent autophagosome formation, and enabling further acidification, fusion with lysosomes and eventual GSDME-NT degradation. Furthermore, in several tumour models, either disturbing Autophagy or interfering with the recognition of GSDME-NT vesicles by targeting TOLLIP increased tumour cell Pyroptosis, activating antitumour immunity and promoting chemotherapeutic efficacy.

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