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  3. CPT1A induction following epigenetic perturbation promotes MAVS palmitoylation and activation to potentiate antitumor immunity

CPT1A induction following epigenetic perturbation promotes MAVS palmitoylation and activation to potentiate antitumor immunity

  • Mol Cell. 2023 Nov 20:S1097-2765(23)00914-0. doi: 10.1016/j.molcel.2023.10.043.
Guiheng Zhang 1,  Peishan Jiang 1,  Wen Tang 2,  Yunyi Wang 3,  Fengqi Qiu 4,  Jie An 1,  Yuping Zheng 5,  Dandan Wu 5,  Jianya Zhou 4,  Dante Neculai 5,  Yang Shi 6,  Wanqiang Sheng 7
Affiliations

Affiliations

  • 1 Institute of Immunology, and Department of Respiratory Disease of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, Zhejiang, China.
  • 2 Department of Human Anatomy, Histology and Embryology, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
  • 3 Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
  • 4 Department of Respiratory Disease of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.
  • 5 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, Zhejiang, China.
  • 6 Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: yang.shi@ludwig.ox.ac.uk.
  • 7 Institute of Immunology, and Department of Respiratory Disease of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, Zhejiang, China. Electronic address: wanqiang_sheng@zju.edu.cn.
PMID: 38016475 DOI: 10.1016/j.molcel.2023.10.043
Abstract

Targeting epigenetic regulators to potentiate anti-PD-1 immunotherapy converges on the activation of type I interferon (IFN-I) response, mimicking cellular response to viral Infection, but how its strength and duration are regulated to impact combination therapy efficacy remains largely unknown. Here, we show that mitochondrial CPT1A downregulation following viral Infection restrains, while its induction by epigenetic perturbations sustains, a double-stranded RNA-activated IFN-I response. Mechanistically, CPT1A recruits the endoplasmic reticulum-localized ZDHHC4 to catalyze MAVS Cys79-palmitoylation, which promotes MAVS stabilization and activation by inhibiting K48- but facilitating K63-linked ubiquitination. Further elevation of CPT1A incrementally increases MAVS palmitoylation and amplifies the IFN-I response, which enhances control of viral Infection and epigenetic perturbation-induced antitumor immunity. Moreover, CPT1A chemical inducers augment the therapeutic effect of combined epigenetic treatment with PD-1 blockade in refractory tumors. Our study identifies CPT1A as a stabilizer of MAVS activation, and its link to epigenetic perturbation can be exploited for Cancer Immunotherapy.

Keywords

CPT1A; DNMTs; LSD1; MAVS; ZDHHC4; double-stranded RNA; epigenetic regulation; palmitoylation; tumor immunity; type I interferon response.

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