PMID- 29244863
OWN - NLM
STAT- MEDLINE
DCOM- 20180625
LR  - 20181113
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 13
IP  - 12
DP  - 2017 Dec
TI  - A parapoxviral virion protein targets the retinoblastoma protein to inhibit NF-kappaB 
      signaling.
PG  - e1006779
LID - 10.1371/journal.ppat.1006779 [doi]
LID - e1006779
AB  - Poxviruses have evolved multiple strategies to subvert signaling by Nuclear 
      Factor kappaB (NF-kappaB), a crucial regulator of host innate immune responses. Here, we 
      describe an orf virus (ORFV) virion-associated protein, ORFV119, which inhibits 
      NF-kappaB signaling very early in infection (</= 30 min post infection). ORFV119 NF-kappaB 
      inhibitory activity was found unimpaired upon translation inhibition, suggesting 
      that virion ORFV119 alone is responsible for early interference in signaling. A 
      C-terminal LxCxE motif in ORFV119 enabled the protein to interact with the 
      retinoblastoma protein (pRb) a multifunctional protein best known for its tumor 
      suppressor activity. Notably, experiments using a recombinant virus containing an 
      ORFV119 mutation which abrogates its interaction with pRb together with 
      experiments performed in cells lacking or with reduced pRb levels indicate that 
      ORFV119 mediated inhibition of NF-kappaB signaling is largely pRb dependent. ORFV119 
      was shown to inhibit IKK complex activation early in infection. Consistent with 
      IKK inhibition, ORFV119 also interacted with TNF receptor associated factor 2 
      (TRAF2), an adaptor protein recruited to signaling complexes upstream of IKK in 
      infected cells. ORFV119-TRAF2 interaction was enhanced in the presence of pRb, 
      suggesting that ORFV119-pRb complex is required for efficient interaction with 
      TRAF2. Additionally, transient expression of ORFV119 in uninfected cells was 
      sufficient to inhibit TNFalpha-induced IKK activation and NF-kappaB signaling, indicating 
      that no other viral proteins are required for the effect. Infection of sheep with 
      ORFV lacking the ORFV119 gene led to attenuated disease phenotype, indicating 
      that ORFV119 contributes to virulence in the natural host. ORFV119 represents the 
      first poxviral protein to interfere with NF-kappaB signaling through interaction with 
      pRb.
FAU - Nagendraprabhu, Ponnuraj
AU  - Nagendraprabhu P
AD  - Department of Pathobiology, College of Veterinary Medicine, University of 
      Illinois at Urbana- Champaign, Urbana, IL, United States of America.
FAU - Khatiwada, Sushil
AU  - Khatiwada S
AD  - Department of Pathobiology, College of Veterinary Medicine, University of 
      Illinois at Urbana- Champaign, Urbana, IL, United States of America.
FAU - Chaulagain, Sabal
AU  - Chaulagain S
AD  - Department of Pathobiology, College of Veterinary Medicine, University of 
      Illinois at Urbana- Champaign, Urbana, IL, United States of America.
FAU - Delhon, Gustavo
AU  - Delhon G
AUID- ORCID: 0000-0002-8694-4103
AD  - School of Veterinary and Biomedical Sciences, Center for Virology, University of 
      Nebraska-Lincoln, Lincoln, NE, United States of America.
FAU - Rock, Daniel L
AU  - Rock DL
AUID- ORCID: 0000-0002-8548-3317
AD  - Department of Pathobiology, College of Veterinary Medicine, University of 
      Illinois at Urbana- Champaign, Urbana, IL, United States of America.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171215
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (NF-kappa B)
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Viral Proteins)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Line
MH  - Cells, Cultured
MH  - Ecthyma, Contagious/etiology
MH  - Gene Knockdown Techniques
MH  - Genes, Viral
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Host-Pathogen Interactions/genetics/immunology/physiology
MH  - Humans
MH  - I-kappa B Kinase/metabolism
MH  - Immunity, Innate
MH  - Mutation
MH  - NF-kappa B/antagonists & inhibitors/*physiology
MH  - Orf virus/genetics/*pathogenicity/*physiology
MH  - Retinoblastoma Protein/antagonists & inhibitors/genetics/*physiology
MH  - Sheep
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 2/metabolism
MH  - Viral Proteins/genetics/immunology/*physiology
MH  - Virulence/genetics/immunology/physiology
PMC - PMC5747488
COIS- The authors have declared that no competing interests exist.
EDAT- 2017/12/16 06:00
MHDA- 2018/06/26 06:00
PMCR- 2017/12/15
CRDT- 2017/12/16 06:00
PHST- 2017/06/26 00:00 [received]
PHST- 2017/11/28 00:00 [accepted]
PHST- 2017/12/29 00:00 [revised]
PHST- 2017/12/16 06:00 [pubmed]
PHST- 2018/06/26 06:00 [medline]
PHST- 2017/12/16 06:00 [entrez]
PHST- 2017/12/15 00:00 [pmc-release]
AID - PPATHOGENS-D-17-01379 [pii]
AID - 10.1371/journal.ppat.1006779 [doi]
PST - epublish
SO  - PLoS Pathog. 2017 Dec 15;13(12):e1006779. doi: 10.1371/journal.ppat.1006779. 
      eCollection 2017 Dec.