Influenza A virus-induced degradation of eukaryotic translation initiation factor 4B contributes to viral replication by suppressing IFITM3 protein expression.
Although alteration in host cellular translation machinery occurs in virus-infected cells, the role of such alteration and the precise pathogenic processes are not well understood. Influenza A virus (IAV) infection shuts off host cell gene expression at transcriptional and translational levels. Here, we found that the protein level of eukaryotic translation initiation factor 4B (eIF4B), an integral component of the translation initiation apparatus, was dramatically reduced in A549 cells as well as in the lung, spleen, and thymus of mice infected with IAV. The decrease in eIF4B level was attributed to lysosomal degradation of eIF4B, which was induced by viral NS1 protein. Silencing eIF4B expression in A549 cells significantly promoted IAV replication, and conversely, overexpression of eIF4B markedly inhibited the viral replication. Importantly, we observed that eIF4B knockdown transgenic mice were more susceptible to IAV infection, exhibiting faster weight loss, shorter survival time, and more-severe organ damage. Furthermore, we demonstrated that eIF4B regulated the expression of interferon-induced transmembrane protein 3 (IFITM3), a critical protein involved in immune defense against a variety of RNA viruses, including influenza virus. Taken together, our findings reveal that eIF4B plays an important role in host defense against IAV infection at least by regulating the expression of IFITM3, which restricts viral entry and thereby blocks early stages of viral production. These data also indicate that influenza virus has evolved a strategy to overcome host innate immunity by downregulating eIF4B protein.


OBJECTIVE
Influenza A virus (IAV) infection stimulates the host innate immune system, in part, by inducing interferons (IFNs). Secreted IFNs activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, leading to elevated transcription of a large group of IFN-stimulated genes that have antiviral function. To circumvent the host innate immune response, influenza virus has evolved multiple strategies for suppressing the production of IFNs. Here, we show that IAV infection induces lysosomal degradation of eIF4B protein; and eIF4B inhibits IAV replication by upregulating expression of interferon-induced transmembrane protein 3 (IFITM3), a key protein that protects the host from virus infection. Our finding illustrates a critical role of eIF4B in the host innate immune response and provides novel insights into the complex mechanisms by which influenza virus interacts with its host.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Song
S
Wang
College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, China.
Xiaojuan
X
Chi
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Haitao
H
Wei
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Yuhai
Y
Chen
College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, China.
Zhilong
Z
Chen
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
Shile
S
Huang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, China chenjl@im.ac.cn.
Ji-Long
JL
Chen
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D004847:Epithelial Cells / Q000821:virology; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D009980:Influenza A virus / Q000502:physiology*; D008168:Lung / Q000473:pathology / Q000821:virology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D014176:Protein Biosynthesis; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000821:virology; D016019:Survival Analysis; D013950:Thymus Gland / Q000821:virology; D014779:Virus Replication
D039642:Eukaryotic Initiation Factors; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C031799:eIF-4B