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

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

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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