2. Academic Validation
  3. HERC5 induces podocyte injury in LN by mediated IRF3 ISGylation to promote the production and overactivation of IFN-β in podocytes

HERC5 induces podocyte injury in LN by mediated IRF3 ISGylation to promote the production and overactivation of IFN-β in podocytes

  • Int Immunopharmacol. 2025 Aug 28:161:115059. doi: 10.1016/j.intimp.2025.115059.
Qun Wei 1,  Li-Wei Wang 2,  Jing Zhao 3,  Yan Dong 4,  Xin-Yan Miao 4,  Yue-Xin Tian 4,  Jin-Xi Liu 4,  Xiao-Juan Feng 4,  Shu-Xia Liu 5,  Qing-Juan Liu 6,  Wei Zhang 7
Affiliations

Affiliations

  • 1 Department of Hospital Infection Control/ Department of Public Health, Hebei General Hospital, Shijiazhuang 050051, China.
  • 2 Department of Pathology, Hebei General Hospital, Shijiazhuang 050051, China.
  • 3 Department of Chinese Medicine and Pharmacology, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China.
  • 4 Department of Pathology, Hebei Key Laboratory of Nephrology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China.
  • 5 Department of Pathology, Hebei Key Laboratory of Nephrology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: shuxialiu@hebmu.edu.cn.
  • 6 Department of Pathology, Hebei Key Laboratory of Nephrology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: 17700562@hebmu.edu.cn.
  • 7 Department of Pathology, Hebei Key Laboratory of Nephrology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: 18300803@hebmu.edu.cn.
PMID: 40505230 DOI: 10.1016/j.intimp.2025.115059
Abstract

Podocytes may mediate local production of Type I interferon (IFN-I), which play a crucial role in the pathogenesis of lupus nephritis (LN). ISGylation is widely involved in the innate immune activation and IFN-I production. Here, we discovered that in patients with LN and pristane-induced model mouse the staining of HERC5, a E3 protein Ligase in ISGylation, was markedly elevated in renal glomerulus and associated with podocyte injury. Knockdown of HERC5 in Human podocyte cells significantly decreased the transcription level of Ifn-b1 and subsequently pro-inflammatory factors Tnf-α, IL-6, and Cxcl10, while increasing anti-inflammatory factor IL-10 levels, and reduced podocyte injury induced by LN plasma or IFN-β. Conversely, overexpression of HERC5 reversed the above results, that increased IFN-β generation and excessive activation, and induced podocyte injury. Mechanistically, HERC5 interacts with and facilitates the ISGylation of IRF3, preventing its ubiquitination and subsequent degradation. This interaction stabilizes IRF3, enhancing its activity and leading to sustained IFN-β production and inflammation. In conclusion, our study identifies HERC5 as a key regulator in LN, promoting IRF3 activation and driving sustained IFN-β production and overactivation. This process induces an inflammatory phenotype in podocytes, contributing to their self-injury.

Keywords

HERC5; IFN-β; IRF3; Lupus nephritis; Podocyte injury.

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