2. Academic Validation
  3. OTUB1 contributes to the stability and function of Influenza A virus NS2

OTUB1 contributes to the stability and function of Influenza A virus NS2

  • PLoS Pathog. 2024 May 30;20(5):e1012279. doi: 10.1371/journal.ppat.1012279.
Yu-Jyun Li 1 2,  Chi-Yuan Chen 1,  Yu-Shen Kuo 1 2,  Yi-Wen Huang 1 2,  Rei-Lin Kuo 3,  Li-Kwan Chang 4,  Jeng-How Yang 5,  Chih-Ho Lai 1 2,  Shin-Ru Shih 3,  Ya-Fang Chiu 1 2 3 5 6
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan.
  • 2 Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
  • 3 Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan.
  • 4 Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan.
  • 5 Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, New Taipei, Taiwan.
  • 6 Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
PMID: 38814988 DOI: 10.1371/journal.ppat.1012279
Abstract

The influenza A virus (IAV) consists of 8 single-stranded, negative-sense viral RNA (vRNA) segments. After Infection, vRNA is transcribed, replicated, and wrapped by viral nucleoprotein (NP) to form viral ribonucleoprotein (vRNP). The transcription, replication, and nuclear export of the viral genome are regulated by the IAV protein, NS2, which is translated from spliced mRNA transcribed from viral NS vRNA. This splicing is inefficient, explaining why NS2 is present in low abundance after IAV Infection. The levels of NS2 and its subsequent accumulation are thought to influence viral RNA replication and vRNP nuclear export. Here we show that NS2 is ubiquitinated at the K64 and K88 residues by K48-linked and K63-linked polyubiquitin (polyUb) chains, leading to the degradation of NS2 by the Proteasome. Additionally, we show that a host Deubiquitinase, OTUB1, can remove polyUb chains conjugated to NS2, thereby stabilizing NS2. Accordingly, knock down of OTUB1 by siRNA reduces the nuclear export of vRNP, and reduces the overall production of IAV. These results collectively demonstrate that the levels of NS2 in IAV-infected cells are regulated by a ubiquitination-deubiquitination system involving OTUB1 that is necessary for optimal IAV replication.

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