2. Academic Validation
  3. ZNF334 truncation mutation drives cold-induced autoinflammation

ZNF334 truncation mutation drives cold-induced autoinflammation

  • EMBO Mol Med. 2025 Oct 30. doi: 10.1038/s44321-025-00328-x.
Joung-Liang Lan 1 2 3,  Shih-Hsin Chang 3 4,  Yi-Hua Lai 1 2 3,  Ju-Pi Li 2 5,  Guan-Jun Chen 6,  Yen-Ju Lin 7 8,  Ya-Ling Huang 6,  Bor-Luen Chiang 9 10,  Jan-Gowth Chang 1 11,  Guan-Yun Lu 6,  Tung-Lin Tsai 12,  Chien-Yu Lin 6,  John Wang 13,  Yi-Chuan Li 14 15,  Mien-Chie Hung 16,  Chin-An Yang 17 18 19 20 21
Affiliations

Affiliations

  • 1 College of Medicine, China Medical University, Taichung, Taiwan.
  • 2 Rheumatic Diseases Research Center, China Medical University Hospital, Taichung, Taiwan.
  • 3 Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan.
  • 4 Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
  • 5 Department of Pathology, School of Medicine, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan.
  • 6 Integrated Precision Health and Immunodiagnostic Center, Department of Laboratory Medicine, China Medical University Hsinchu Hospital, Zhubei City, Taiwan.
  • 7 Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
  • 8 Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
  • 9 Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 10 Genome and Systems Biology Degree Program, College of Life Science, National Taiwan University, Taipei, Taiwan.
  • 11 Department of Research and Development, Show Chwan Healthcare System, Changhua, Taiwan.
  • 12 Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan.
  • 13 Department of Pathology, China Medical University Hospital, Taichung, Taiwan.
  • 14 Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
  • 15 Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan.
  • 16 Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
  • 17 College of Medicine, China Medical University, Taichung, Taiwan. yangca@cgmh.org.tw.
  • 18 Integrated Precision Health and Immunodiagnostic Center, Department of Laboratory Medicine, China Medical University Hsinchu Hospital, Zhubei City, Taiwan. yangca@cgmh.org.tw.
  • 19 Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan. yangca@cgmh.org.tw.
  • 20 Department of Pediatrics, China Medical University Hsinchu Hospital, Zhubei City, Taiwan. yangca@cgmh.org.tw.
  • 21 Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan. yangca@cgmh.org.tw.
PMID: 41168503 DOI: 10.1038/s44321-025-00328-x
Abstract

The role of Zinc Finger Protein 334 (ZNF334) in immunological processes remains unknown. We identified a ZNF334 truncation mutation (p.Thr399fs) in a rare case of late-onset cold-induced autoinflammatory disease with elevated TNF-α, IL-1β, IL-6, and extracellular heat shock protein 90 (eHsp90) plasma levels and progressive sensorineural hearing loss. Using patient-derived monocytes and CRISPR/Cas9-edited THP-1 monocytes with a ZNF334 truncation mutation, we discovered that the mutation reduced the interaction between ZNF334 and HSP90, diminished the endogenous levels of the cold stress regulators HSP90 and transient receptor potential melastatin 8 (TRPM8), disrupted ER protein folding response and redox homeostasis, and increased cold-induced NF-κB activation and secretion of the proinflammatory TRPM8+ mitochondria-containing extracellular vesicles in monocytes. Long-term cold avoidance alleviated the patient's cold-induced symptoms. In addition, treatment of ZNF334-truncated THP-1 cells with an HSP90 Inhibitor prevented cold-induced TNF and NLRP3 upregulations. Our findings suggest ZNF334 as an essential regulator of cold-induced inflammation and oxidative stress, and HSP90 ATPase inhibitors might be effective in the treatment of autoinflammatory diseases induced by repeated mild cold exposure.

Keywords

Autoinflammation; Cold; Mutation; Sensorineural Hearing Loss; ZNF334.

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