2. Academic Validation
  3. TOLLIP targets GSDME-NT-carrying endocytic vesicles for autophagy to regulate pyroptosis and chemotherapy efficacy

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

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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