SARS-CoV-2 rORF3, a novel microprotein, impairs interferon-β production by targeting RanBP2 to inhibit p65 nuclear import

  • Int J Biol Macromol. 2026 Feb;344(Pt 2):150557. doi: 10.1016/j.ijbiomac.2026.150557.
Yucong Huang  1 ,  Jing Jiang  1 ,  Qingting Xiao  1 ,  Yajie Wang  1 ,  Gulinaziya Abulaike  1 ,  Ayinuer Maimaiti  1 ,  Pan Gong  2 ,  Xiaohuang Lin  3 ,  Fangfang Li  2 ,  Xueping Zhou  2 ,  Alexander F Palazzo  4 ,  Qingtang Shen  5
Affiliations
  • 1. Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108, China.
  • 2. State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
  • 3. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China.
  • 4. Department of Biochemistry, University of Toronto, Toronto, ON, M5G 1M1, Canada.
  • 5. Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108, China. Electronic address: [email protected].
PMID: 41611154 DOI: 10.1016/j.ijbiomac.2026.150557
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes various proteins to evade host innate immunity. rORF3 is a novel microprotein encoded by the negative-strand RNA (-RNA) of SARS-CoV-2 that antagonizes type I interferon (IFN-I) production. However, the molecular mechanism by which SARS-CoV-2 rORF3 suppresses IFN-I production remains elusive. Here we report rORF3 interacts with a nucleoporin Ran-Binding Protein 2 (RanBP2), and suppresses IFN-β production and promotes Viral Infection in a RanBP2-dependent manner. Specifically, we found RanBP2 inhibits the RIG-I-like Receptor (RLR)-mediated signaling by targeting p65 and suppressing the nuclear translocation of p65. rORF3 targets RanBP2 and impedes the nuclear translocation of p65 upon tumor necrosis factor-alpha (TNF-α) stimulation, thereby antagonizing IFN-β production. Our findings not only reveal a novel function of RanBP2 in regulating RLR signaling but also provide insights into a new mechanism of the innate immune evasion by SARS-CoV-2.

Keywords
Innate immunity; Microprotein; RanBP2; Severe acute respiratory syndrome coronavirus 2; p65; rORF3.
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