Rotavirus nonstructural protein 1 suppresses virus-induced cellular apoptosis to facilitate viral growth by activating the cell survival pathways during early stages of infection.
Following virus infection, one of the cellular responses to limit the virus spread is induction of apoptosis. In the present study, we report role of rotavirus nonstructural protein 1 (NSP1) in regulating apoptosis by activating prosurvival pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt and NF-kappaB (nuclear factor kappaB) during early hours of infections (2 to 8 hpi). The NSP1 mutant strain A5-16 induces weak and transient activation of Akt (protein kinase B) and p65 NF-kappaB compared to the isogenic wild-type strain A5-13 in MA104 or HT29 cells. The weak NF-kappaB promoter activity or Akt phosphorylation after A5-16 infection could be complemented in cells transfected with plasmid expressing NSP1 after infection with the rotavirus A5-16 strain. In cells either infected with A5-13 or transfected with pcD-NSP1, coimmunoprecipitation of NSP1 with phosphoinositide 3-kinase (PI3K) was observed, indicating that strong activation of PI3K/Akt could be due to its interaction with NSP1. In addition, after infection with same multiplicity of infection, A5-16 showed reduced number of viral particles compared to the A5-13 strain at the end of the replication cycle. A lower growth rate could be due to weak induction of PI3K/Akt and NF-kappaB, since the A5-13 strain also showed reduced growth in the presence of PI3K or NF-kappaB inhibitors. This effect was interferon independent; however, it was partly due to significantly higher caspase-3 activity, poly-ADP ribose polymerase (PARP) cleavage, and apoptosis during earlier stages of infection with the NSP1 mutant. Thus, our data suggest that NSP1 positively supports rotavirus growth by suppression of premature apoptosis for improved virus growth after infection.
Bagchi
Parikshit
P
Division of Virology, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme-XM, Beliaghata, Kolkata 700010, West Bengal, India.
Dutta
Dipanjan
D
Chattopadhyay
Shiladitya
S
Mukherjee
Anupam
A
Halder
Umesh Chandra
UC
Sarkar
Sagartirtha
S
Kobayashi
Nobumichi
N
Komoto
Satoshi
S
Taniguchi
Koki
K
Chawla-Sarkar
Mamta
M
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D000882:Haplorhini; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D012401:Rotavirus / Q000254:growth & development / Q000472:pathogenicity*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; D019869:Phosphatidylinositol 3-Kinases
J Virol. 2009 Jul;83(13):6883-99
19386722
J Virol. 2008 Jan;82(1):148-60
17942548
J Biol Chem. 2002 Jan 4;277(1):492-501
11687577
Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14194-9
16963558
Virology. 1993 Sep;196(1):372-8
8395125
Eur J Immunol. 2005 Jul;35(7):2200-9
15940673
PLoS Med. 2007 Apr;4(4):e121
17439294
Virus Res. 2004 Apr;101(1):67-81
15010218
Nat Immunol. 2006 Feb;7(2):131-7
16424890
J Virol. 2000 Sep;74(17):7989-96
10933707
J Virol. 2004 Apr;78(8):4363-9
15047850
J Virol. 2008 Apr;82(7):3796-802
18216097
J Immunol. 1999 Oct 15;163(8):4442-52
10510386
J Virol. 2009 Oct;83(20):10322-35
19656876
J Virol. 2009 Jul;83(14):6987-94
19420080
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6288-92
7912826
Virology. 2000 Sep 15;275(1):89-97
11017790
J Virol. 2007 Apr;81(7):3058-67
17229704
J Gen Virol. 1979 Jun;43(3):513-9
225432
PLoS Pathog. 2009 Jan;5(1):e1000280
19180189
J Biol Chem. 2004 Mar 26;279(13):12232-41
14709551
J Virol. 1994 Jun;68(6):3821-9
7514679
Virology. 2009 Sep 1;391(2):325-33
19628238
Science. 2003 May 16;300(5622):1145-8
12702807
Cell Death Differ. 2004 Aug;11(8):915-23
15118763
J Pediatr Gastroenterol Nutr. 1998 Jul;27(1):123-4
9669745
J Virol. 2004 Feb;78(4):1865-72
14747551
Virology. 2005 Jan 5;331(1):73-81
15582654
Apoptosis. 2003 Jun;8(3):237-49
12766484
J Virol. 2008 Nov;82(22):11283-93
18799579
Annu Rev Microbiol. 1999;53:577-628
10547702
J Virol. 2003 Jul;77(14):7945-56
12829834
J Virol. 2007 Feb;81(4):1786-95
17151097
J Virol. 1996 Jun;70(6):4125-30
8648754
Endocrinology. 2000 Dec;141(12):4503-11
11108261
Curr Opin Microbiol. 2001 Aug;4(4):435-41
11495808
J Immunol. 1999 Aug 1;163(3):1457-66
10415047
Nature. 1999 Sep 2;401(6748):82-5
10485710
J Virol. 2004 Sep;78(18):9721-30
15331705
J Biol Chem. 2001 Jun 8;276(23):19889-96
11262403
Cell. 1993 Mar 12;72(5):767-78
7680959
J Mol Biol. 2009 Jan 9;385(1):140-52
18976670
Circ Res. 2000 Oct 13;87(8):677-82
11029403
J Interferon Cytokine Res. 1999 Jan;19(1):1-13
10048763
J Gen Virol. 2007 Mar;88(Pt 3):942-950
17325368
Genes Dev. 1999 Nov 15;13(22):2905-27
10579998
Cell Microbiol. 2007 Oct;9(10):2358-71
17848167
J Gen Virol. 2004 May;85(Pt 5):1065-1076
15105524
J Virol. 2005 Jul;79(13):8388-99
15956583
Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4114-9
15741273
Cell Microbiol. 2009 Jun;11(6):863-71
19290913
J Virol. 2009 May;83(10):4942-51
19244315
J Virol. 2007 May;81(9):4473-81
17301153