title: Rotavirus-encoded nonstructural protein 1 modulates cellular apoptotic machinery by targeting tumor suppressor protein p53.
abstract: p53, a member of the innate immune system, is triggered under stress to induce cell growth arrest and apoptosis. Thus, p53 is an important target for viruses, as efficient infection depends on modulation of the host apoptotic machinery. This study focuses on how rotaviruses manipulate intricate p53 signaling for their advantage. Analysis of p53 expression revealed degradation of p53 during initial stages of rotavirus infection. However, in nonstructural protein-1 (NSP1) mutant strain A5-16, p53 degradation was not observed, suggesting a role of NSP1 in this process. This function of NSP1 was independent of its interferon or phosphatidylinositol 3-kinase (PI3K)/AKT modulation activity since p53 degradation was observed in Vero cells as well as in the presence of PI3K inhibitor. p53 transcript levels remained the same in SA11-infected cells (at 2 to 14 h postinfection), but p53 protein was stabilized only in the presence of MG132, suggesting a posttranslational process. NSP1 interacted with the DNA binding domain of p53, resulting in ubiquitination and proteasomal degradation of p53. Degradation of p53 during initial stages of infection inhibited apoptosis, as the proapoptotic genes PUMA and Bax were downregulated. During late viral infection, when progeny dissemination is the main objective, the NSP1-p53 interaction was diminished, resulting in restoration of the p53 level, with initiation of proapoptotic signaling ensuing. Overall results highlight the multiple strategies evolved by NSP1 to combat the host immune response.
authors.affiliation: Division of Virology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhowmick
authors.forename: Umesh Chandra
authors.initials: UC
authors.lastname: Halder
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Mukti Kant
authors.initials: MK
authors.lastname: Nayak
authors.forename: Mamta
authors.initials: M
authors.lastname: Chawla-Sarkar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000821:virology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000821:virology; D012401:Rotavirus / Q000235:genetics / Q000472:pathogenicity*; D012400:Rotavirus Infections / Q000821:virology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; C104282:nsp1 protein, Rotavirus