PMID- 22258253
OWN - NLM
STAT- MEDLINE
DCOM- 20120611
LR  - 20211021
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 86
IP  - 7
DP  - 2012 Apr
TI  - Nonstructural protein 2 of porcine reproductive and respiratory syndrome virus 
      inhibits the antiviral function of interferon-stimulated gene 15.
PG  - 3839-50
LID - 10.1128/JVI.06466-11 [doi]
AB  - Type I interferon (alpha/beta interferon [IFN-alpha/beta]) stimulates the expression of 
      interferon-stimulated gene 15 (ISG15), which encodes a ubiquitin-like protein, 
      ISG15. Free ISG15 and ISG15 conjugates function in diverse cellular pathways, 
      particularly regulation of antiviral innate immune responses. In this study, we 
      demonstrate that ISG15 overexpression inhibits porcine reproductive and 
      respiratory syndrome virus (PRRSV) replication in cell culture and that the 
      antiviral activity of interferon is reduced by inhibition of ISG15 conjugation. 
      PRRSV nonstructural protein 2 (nsp2) was previously identified as a potential 
      antagonist of ISG15 production and conjugation. The protein contains a 
      papain-like protease domain (PLP2) that plays a crucial role in the proteolytic 
      cleavage of the PRRSV replicase polyproteins. PLP2 was also proposed to belong to 
      the ovarian tumor domain-containing superfamily of deubiquitinating enzymes 
      (DUBs), which is capable of inhibiting ISG15 production and counteracting ISG15 
      conjugation to cellular proteins. To determine whether this immune antagonist 
      function could be selectively inactivated, we engineered a panel of mutants with 
      deletions and/or mutations at the N-terminal border of the nsp2 PLP2-DUB domain. 
      A 23-amino-acid deletion (amino acids 402 to 424 of the ORF1a-encoded protein) 
      largely abolished the inhibitory effect of nsp2 on ISG15 production and 
      conjugation, but no viable recombinant virus was recovered. A 19-amino-acid 
      deletion (amino acids 402 to 420), in combination with a downstream point 
      mutation (S465A), partially relieved the ISG15 antagonist function and yielded a 
      viable recombinant virus. Taken together, our data demonstrate that ISG15 and 
      ISGylation play an important role in the response to PRRSV infection and that 
      nsp2 is a key factor in counteracting the antiviral function of ISG15.
FAU - Sun, Zhi
AU  - Sun Z
AD  - Department of Veterinary and Biomedical Science/Department of 
      Biology-Microbiology, South Dakota State University, Brookings, South Dakota, 
      USA.
FAU - Li, Yanhua
AU  - Li Y
FAU - Ransburgh, Russell
AU  - Ransburgh R
FAU - Snijder, Eric J
AU  - Snijder EJ
FAU - Fang, Ying
AU  - Fang Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120118
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Cytokines)
RN  - 0 (Interferon Type I)
RN  - 0 (Ubiquitins)
RN  - 0 (Viral Nonstructural Proteins)
RN  - 60267-61-0 (ISG15 protein, human)
SB  - IM
MH  - Animals
MH  - Cytokines/antagonists & inhibitors/genetics/*immunology
MH  - *Down-Regulation
MH  - Interferon Type I/immunology
MH  - Porcine Reproductive and Respiratory Syndrome/genetics/*immunology/virology
MH  - Porcine respiratory and reproductive syndrome virus/genetics/*immunology
MH  - Swine
MH  - Ubiquitins/antagonists & inhibitors/genetics/*immunology
MH  - Viral Nonstructural Proteins/genetics/*immunology
PMC - PMC3302520
EDAT- 2012/01/20 06:00
MHDA- 2012/06/12 06:00
PMCR- 2012/10/01
CRDT- 2012/01/20 06:00
PHST- 2012/01/20 06:00 [entrez]
PHST- 2012/01/20 06:00 [pubmed]
PHST- 2012/06/12 06:00 [medline]
PHST- 2012/10/01 00:00 [pmc-release]
AID - JVI.06466-11 [pii]
AID - 06466-11 [pii]
AID - 10.1128/JVI.06466-11 [doi]
PST - ppublish
SO  - J Virol. 2012 Apr;86(7):3839-50. doi: 10.1128/JVI.06466-11. Epub 2012 Jan 18.