PMID- 31167906
OWN - NLM
STAT- MEDLINE
DCOM- 20200603
LR  - 20220716
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 93
IP  - 16
DP  - 2019 Aug 15
TI  - Programmed -2/-1 Ribosomal Frameshifting in Simarteriviruses: an Evolutionarily 
      Conserved Mechanism.
LID - 10.1128/JVI.00370-19 [doi]
LID - e00370-19
AB  - The -2/-1 programmed ribosomal frameshifting (-2/-1 PRF) mechanism in porcine 
      reproductive and respiratory syndrome virus (PRRSV) leads to the translation of 
      two additional viral proteins, nonstructural protein 2TF (nsp2TF) and nsp2N. This 
      -2/-1 PRF mechanism is transactivated by a viral protein, nsp1beta, and cellular 
      poly(rC) binding proteins (PCBPs). Critical elements for -2/-1 PRF, including a 
      slippery sequence and a downstream C-rich motif, were also identified in 11 
      simarteriviruses. However, the slippery sequences (XXXUCUCU instead of XXXUUUUU) 
      in seven simarteriviruses can only facilitate -2 PRF to generate nsp2TF. The 
      nsp1beta of simian hemorrhagic fever virus (SHFV) was identified as a key factor 
      that transactivates both -2 and -1 PRF, and the universally conserved Tyr111 and 
      Arg114 in nsp1beta are essential for this activity. In vitro translation experiments 
      demonstrated the involvement of PCBPs in simarterivirus -2/-1 PRF. Using SHFV 
      reverse genetics, we confirmed critical roles of nsp1beta, slippery sequence, and 
      C-rich motif in -2/-1 PRF in SHFV-infected cells. Attenuated virus growth ability 
      was observed in SHFV mutants with impaired expression of nsp2TF and nsp2N. 
      Comparative genomic sequence analysis showed that key elements of -2/-1 PRF are 
      highly conserved in all known arteriviruses except equine arteritis virus (EAV) 
      and wobbly possum disease virus (WPDV). Furthermore, -2/-1 PRF with SHFV PRF 
      signal RNA can be stimulated by heterotypic nsp1betas of all non-EAV arteriviruses 
      tested. Taken together, these data suggest that -2/-1 PRF is an evolutionarily 
      conserved mechanism employed in non-EAV/-WPDV arteriviruses for the expression of 
      additional viral proteins that are important for viral replication.IMPORTANCE 
      Simarteriviruses are a group of arteriviruses infecting nonhuman primates, and a 
      number of new species have been established in recent years. Although these 
      arteriviruses are widely distributed among African nonhuman primates of different 
      species, and some of them cause lethal hemorrhagic fever disease, this group of 
      viruses has been undercharacterized. Since wild nonhuman primates are 
      historically important sources or reservoirs of human pathogens, there is concern 
      that simarteriviruses may be preemergent zoonotic pathogens. Thus, molecular 
      characterization of simarteriviruses is becoming a priority in arterivirology. In 
      this study, we demonstrated that an evolutionarily conserved ribosomal 
      frameshifting mechanism is used by simarteriviruses and other distantly related 
      arteriviruses for the expression of additional viral proteins. This mechanism is 
      unprecedented in eukaryotic systems. Given the crucial role of ribosome function 
      in all living systems, the potential impact of the in-depth characterization of 
      this novel mechanism reaches beyond the field of virology.
CI  - Copyright (c) 2019 Li et al.
FAU - Li, Yanhua
AU  - Li Y
AD  - Department of Diagnostic Medicine and Pathobiology, Kansas State University, 
      Manhattan, Kansas, USA.
AD  - Division of Virology, Department of Pathology, University of Cambridge, 
      Cambridge, United Kingdom.
FAU - Firth, Andrew E
AU  - Firth AE
AUID- ORCID: 0000-0002-7986-9520
AD  - Division of Virology, Department of Pathology, University of Cambridge, 
      Cambridge, United Kingdom.
FAU - Brierley, Ian
AU  - Brierley I
AD  - Division of Virology, Department of Pathology, University of Cambridge, 
      Cambridge, United Kingdom.
FAU - Cai, Yingyun
AU  - Cai Y
AD  - Integrated Research Facility at Fort Detrick, National Institute of Allergy and 
      Infectious Diseases, National Institutes of Health, Frederick, Maryland, USA.
FAU - Napthine, Sawsan
AU  - Napthine S
AD  - Division of Virology, Department of Pathology, University of Cambridge, 
      Cambridge, United Kingdom.
FAU - Wang, Tao
AU  - Wang T
AD  - Department of Diagnostic Medicine and Pathobiology, Kansas State University, 
      Manhattan, Kansas, USA.
AD  - Yangzhou University, Yangzhou, People's Republic of China.
FAU - Yan, Xingyu
AU  - Yan X
AD  - Department of Diagnostic Medicine and Pathobiology, Kansas State University, 
      Manhattan, Kansas, USA.
FAU - Kuhn, Jens H
AU  - Kuhn JH
AD  - Integrated Research Facility at Fort Detrick, National Institute of Allergy and 
      Infectious Diseases, National Institutes of Health, Frederick, Maryland, USA.
FAU - Fang, Ying
AU  - Fang Y
AD  - Department of Diagnostic Medicine and Pathobiology, Kansas State University, 
      Manhattan, Kansas, USA yfang@vet.k-state.edu.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - 106207/WT_/Wellcome Trust/United Kingdom
GR  - 646891/ERC_/European Research Council/International
GR  - HHSN272200700016I/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190730
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Viral Nonstructural Proteins)
SB  - IM
MH  - Amino Acid Motifs
MH  - Amino Acid Sequence
MH  - Animals
MH  - Arterivirus/genetics
MH  - *Biological Evolution
MH  - Cell Line
MH  - *Frameshifting, Ribosomal
MH  - Gene Expression
MH  - Models, Molecular
MH  - Porcine respiratory and reproductive syndrome virus/*genetics
MH  - Protein Conformation
MH  - Structure-Activity Relationship
MH  - Viral Nonstructural Proteins/chemistry/genetics/metabolism
MH  - Virus Replication
PMC - PMC6675879
OTO - NOTNLM
OT  - arterivirus
OT  - simarterivirus
OT  - -2/-1 programmed ribosomal frameshifting
EDAT- 2019/06/07 06:00
MHDA- 2020/06/04 06:00
PMCR- 2019/07/30
CRDT- 2019/06/07 06:00
PHST- 2019/03/06 00:00 [received]
PHST- 2019/05/29 00:00 [accepted]
PHST- 2019/06/07 06:00 [pubmed]
PHST- 2020/06/04 06:00 [medline]
PHST- 2019/06/07 06:00 [entrez]
PHST- 2019/07/30 00:00 [pmc-release]
AID - JVI.00370-19 [pii]
AID - 00370-19 [pii]
AID - 10.1128/JVI.00370-19 [doi]
PST - epublish
SO  - J Virol. 2019 Jul 30;93(16):e00370-19. doi: 10.1128/JVI.00370-19. Print 2019 Aug 
      15.