title: Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin.
abstract: Apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death. The nucleoprotein (NP) of IAV is known to contribute to viral pathogenesis, but its role in virus-induced host cell death was hitherto unknown. We observed that NP contributes to IAV infection induced cell death and heterologous expression of NP alone can induce apoptosis in human airway epithelial cells. The apoptotic effect of IAV NP was significant when compared with other known proapoptotic proteins of IAV. The cell death induced by IAV NP was executed through the intrinsic apoptosis pathway. We screened host cellular factors for those that may be targeted by NP for inducing apoptosis and identified human antiapoptotic protein Clusterin (CLU) as a novel interacting partner. The interaction between IAV NP and CLU was highly conserved and mediated through β-chain of the CLU protein. Also CLU was found to interact specifically with IAV NP and not with any other known apoptosis modulatory protein of IAV. CLU prevents induction of the intrinsic apoptosis pathway by binding to Bax and inhibiting its movement into the mitochondria. We found that the expression of IAV NP reduced the association between CLU and Bax in mammalian cells. Further, we observed that CLU overexpression attenuated NP-induced cell death and had a negative effect on IAV replication. Collectively, these findings indicate a new function for IAV NP in inducing host cell death and suggest a role for the host antiapoptotic protein CLU in this process.
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Tripathi
authors.forename: J
authors.initials: J
authors.lastname: Batra
authors.forename: W
authors.initials: W
authors.lastname: Cao
authors.forename: K
authors.initials: K
authors.lastname: Sharma
authors.forename: J R
authors.initials: JR
authors.lastname: Patel
authors.forename: P
authors.initials: P
authors.lastname: Ranjan
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.forename: J M
authors.initials: JM
authors.lastname: Katz
authors.forename: N J
authors.initials: NJ
authors.lastname: Cox
authors.forename: R B
authors.initials: RB
authors.lastname: Lal
authors.forename: S
authors.initials: S
authors.lastname: Sambhara
authors.forename: S K
authors.initials: SK
authors.lastname: Lal
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria; D019590:Nucleocapsid Proteins; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C495242:CLU protein, human; D051152:Clusterin; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D051028:bcl-2-Associated X Protein
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