Interaction of NS2 with AIMP2 facilitates the switch from ubiquitination to SUMOylation of M1 in influenza A virus-infected cells.

Abstract

UNLABELLED:

Influenza A viruses (IAVs) rely on host factors to support their life cycle, as viral proteins hijack or interact with cellular proteins to execute their functions. Identification and understanding of these factors would increase our knowledge of the molecular mechanisms manipulated by the viruses. In this study, we searched for novel binding partners of the influenza A virus NS2 protein, the nuclear export protein responsible for overcoming host range restriction, by a yeast two-hybrid screening assay and glutathione S-transferase-pulldown and coimmunoprecipitation assays and identified AIMP2, a potent tumor suppressor that usually functions to regulate protein stability, as one of the major NS2-binding candidates. We found that the presence of NS2 protected AIMP2 from ubiquitin-mediated degradation in NS2-transfected cells and AIMP2 functioned as a positive regulator of IAV replication. Interestingly, AIMP2 had no significant effect on NS2 but enhanced the stability of the matrix protein M1. Further, we provide evidence that AIMP2 recruitment switches the modification of M1 from ubiquitination to SUMOylation, which occurs on the same attachment site (K242) on M1 and thereby promotes M1-mediated viral ribonucleoprotein complex nuclear export to increase viral replication. Collectively, our results reveal a new mechanism of AIMP2 mediation of influenza virus replication.

IMPORTANCE:

Although the ubiquitination of M1 during IAV infection has been observed, the precise modification site and the molecular consequences of this modification remain obscure. Here, we demonstrate for the first time that ubiquitin and SUMO compete for the same lysine (K242) on M1 and the interaction of NS2 with AIMP2 facilitates the switch of the M1 modification from ubiquitination to SUMOylation, thus increasing viral replication.

• Authors: Shijuan Gao, Jiaoxiang Wu, Ran-Yi Liu, Jiandong Li, Liping Song, Yan Teng, Chunjie Sheng, Dong Liu, Chen Yao, Huiming Chen, Wei Jiang, Shuai Chen, Wenlin Huang
• Journal: Journal of virology (J Virol) Vol. 89 Issue 1 Pg. 300-11 (Jan 2015) ISSN: 1098-5514 [Electronic] United States
• PMID: 25320310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• AIMP2 protein, human
• M1 protein, Influenza A virus
• NS2 protein, influenza virus A
• Nuclear Proteins
• Viral Matrix Proteins
• Viral Nonstructural Proteins

Topics

• Cell Line
• Centrifugation
• Host-Pathogen Interactions
• Humans
• Immunoprecipitation
• Influenza A virus (physiology)
• Nuclear Proteins (metabolism)
• Protein Binding
• Protein Interaction Mapping
• Sumoylation
• Two-Hybrid System Techniques
• Ubiquitination
• Viral Matrix Proteins (metabolism)
• Viral Nonstructural Proteins (metabolism)
• Virus Replication