Robust expression of vault RNAs induced by influenza A virus plays a critical role in suppression of PKR-mediated innate immunity.
Protein kinase R (PKR) is a vital component of host innate immunity against viral infection. However, the mechanism underlying inactivation of PKR by inﬂuenza A virus (IAV) remains elusive. Here, we found that vault RNAs (vtRNAs) were greatly induced in A549 cells and mouse lungs after infection with IAV. The viral NS1 protein was shown to be the inducer triggering the upregulation of vtRNAs. Importantly, silencing vtRNA in A549 cells significantly inhibited IAV replication, whereas overexpression of vtRNAs markedly promoted the viral replication. Furthermore, in vivo studies showed that disrupting vtRNA expression in mice significantly decreased IAV replication in infected lungs. The vtRNA knockdown animals exhibited significantly enhanced resistance to IAV infection, as evidenced by attenuated acute lung injury and spleen atrophy and consequently increased survival rates. Interestingly, vtRNAs promoted viral replication through repressing the activation of PKR and the subsequent antiviral interferon response. In addition, increased expression of vtRNAs was required for efficient suppression of PKR by NS1 during IAV infection. Moreover, vtRNAs were also significantly upregulated by infections of several other viruses and involved in the inactivation of PKR signaling by these viruses. These results reveal a novel mechanism by which some viruses circumvent PKR-mediated innate immunity.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
Fang
F
Li
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
Yuhai
Y
Chen
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China School of Life Sciences, Anhui University, Hefei 230601, China.
Zhaoyuan
Z
Zhang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
Jing
J
Ouyang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
Yi
Y
Wang
College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
Ruoxiang
R
Yan
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Shile
S
Huang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
George Fu
GF
Gao
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
Guijie
G
Guo
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China chenjl@im.ac.cn.
Ji-Long
JL
Chen
D000818:Animals; D002460:Cell Line; D060467:Disease Resistance; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000502:physiology*; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism*
C085820:INS1 protein, influenza virus; D022661:RNA, Untranslated; D017361:Viral Nonstructural Proteins; D007372:Interferons; D019892:eIF-2 Kinase