title: The nucleoprotein of influenza A virus induces p53 signaling and apoptosis via attenuation of host ubiquitin ligase RNF43.
abstract: The interplay between influenza virus and host factors to support the viral life cycle is well documented. Influenza A virus (IAV) proteins interact with an array of cellular proteins and hijack host pathways which are at the helm of cellular responses to facilitate virus invasion. The multifaceted nature of the ubiquitination pathway for protein regulation makes it a vulnerable target of many viruses including IAV. To this end we conducted a yeast two-hybrid screen to search for cellular ubiquitin ligases important for influenza virus replication. We identified host protein, RING finger protein 43 (RNF43), a RING-type E3 ubiquitin ligase, as a novel interactor of nucleoprotein (NP) of IAV and an essential partner to induce NP-driven p53-mediated apoptosis in IAV-infected cells. In this study, we demonstrate that IAV leads to attenuation of RNF43 transcripts and hence its respective protein levels in the cellular milieu whereas in RNF43 depleted cells, viral replication was escalated several folds. Moreover, RNF43 polyubiquitinates p53 which further leads to its destabilization resulting in a decrease in induction of the p53 apoptotic pathway, a hitherto unknown process targeted by NP for p53 stabilization and accumulation. Collectively, these results conclude that NP targets RNF43 to modulate p53 ubiquitination levels and hence causes p53 stabilization which is conducive to an enhanced apoptosis level in the host cells. In conclusion, our study unravels a novel strategy adopted by IAV for utilizing the much conserved ubiquitin proteasomal pathway.
authors.affiliation: School of Science, Monash University Malaysia, Bandar Sunway, 47500 Petaling Jaya, Selangor DE, Malaysia.
authors.forename: H
authors.initials: H
authors.lastname: Nailwal
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Mayank
authors.affiliation: 1] School of Science, Monash University Malaysia, Bandar Sunway, 47500 Petaling Jaya, Selangor DE, Malaysia [2] Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Lal
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000378:metabolism; D019590:Nucleocapsid Proteins; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D014758:Viral Core Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D014758:Viral Core Proteins; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases