PMID:24551175

Citation	Jefferson, M, Whelband, M, Mohorianu, I and Powell, PP (2014) The Pestivirus N Terminal Protease N(pro) Redistributes to Mitochondria and Peroxisomes Suggesting New Sites for Regulation of IRF3 by N(pro.). PLoS ONE 9:e88838
Abstract	The N-terminal protease of pestiviruses, N(pro) is a unique viral protein, both because it is a distinct autoprotease that cleaves itself from the following polyprotein chain, and also because it binds and inactivates IRF3, a central regulator of interferon production. An important question remains the role of N(pro) in the inhibition of apoptosis. In this study, apoptotic signals induced by staurosporine, interferon, double stranded RNA, sodium arsenate and hydrogen peroxide were inhibited by expression of wild type N(pro), but not by mutant protein N(pro) C112R, which we show is less efficient at promoting degradation of IRF3, and led to the conclusion that N(pro) inhibits the stress-induced intrinsic mitochondrial pathway through inhibition of IRF3-dependent Bax activation. Both expression of N(pro) and infection with Bovine Viral Diarrhea Virus (BVDV) prevented Bax redistribution and mitochondrial fragmentation. Given the role played by signaling platforms during IRF3 activation, we have studied the subcellular distribution of N(pro) and we show that, in common with many other viral proteins, N(pro) targets mitochondria to inhibit apoptosis in response to cell stress. N(pro) itself not only relocated to mitochondria but in addition, both N(pro) and IRF3 associated with peroxisomes, with over 85% of N(pro) puncta co-distributing with PMP70, a marker for peroxisomes. In addition, peroxisomes containing N(pro) and IRF3 associated with ubiquitin. IRF3 was degraded, whereas N(pro) accumulated in response to cell stress. These results implicate mitochondria and peroxisomes as new sites for IRF3 regulation by N(pro), and highlight the role of these organelles in the anti-viral pathway.
Links	PubMed PMC3925175 Online version:10.1371/journal.pone.0088838
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
BVDV:A0N0F0		GO:0043653: mitochondrial fragmentation involved in apoptotic process	ECO:0000315:		P		the Npro protein prevent fragmentation of mitochondria to inhibit apoptosis in response to cell stress in fig 2.	complete CACAO 9536
BVDV:A0N0F0		GO:0043066: negative regulation of apoptotic process	ECO:0000315:		P		Inhibition of apoptosis by Npro correlates with degradation of IRF3 in fig 1.	complete CACAO 9581
BVDV:A0N0F0	involved_in	GO:0043066: negative regulation of apoptotic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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