2. Academic Validation
  3. The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome

The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome

  • EMBO J. 2024 Nov;43(22):5469-5493. doi: 10.1038/s44318-024-00236-9.
Jing Huang # 1,  Yao Wang # 2,  Xin Jia 3,  Changfeng Zhao 1,  Meiqi Zhang 3,  Mi Bao 1,  Pan Fu 1,  Cuiqin Cheng 3,  Ruona Shi 4 5,  Xiaofei Zhang 4 5,  Jun Cui 1,  Gang Wan 6,  Anlong Xu 7 8
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China.
  • 2 Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. yaowang@bucm.edu.cn.
  • 3 Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 4 CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, 510530, China.
  • 5 Center for Cell Lineage and Atlas, BioLand Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong, 510530, China.
  • 6 Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China. wangang5@mail.sysu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China. lssxal@mail.sysu.edu.cn.
  • 8 Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China. lssxal@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39333773 DOI: 10.1038/s44318-024-00236-9
Abstract

Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by Caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.

Keywords

Feed-Forward Loop; Genetic Disease; Hyperinflammation; NLRP3 Inflammasome; ZNFX1.

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