PMID- 29444946
OWN - NLM
STAT- MEDLINE
DCOM- 20180517
LR  - 20191210
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 92
IP  - 9
DP  - 2018 May 1
TI  - Karyopherin Alpha 6 Is Required for Replication of Porcine Reproductive and 
      Respiratory Syndrome Virus and Zika Virus.
LID - 10.1128/JVI.00072-18 [doi]
LID - e00072-18
AB  - Movement of macromolecules between the cytoplasm and the nucleus occurs through 
      the nuclear pore complex (NPC). Karyopherins comprise a family of soluble 
      transport factors facilitating the nucleocytoplasmic translocation of proteins 
      through the NPC. In this study, we found that karyopherin alpha6 (KPNA6; also known 
      as importin alpha7) was required for the optimal replication of porcine reproductive 
      and respiratory syndrome virus (PRRSV) and Zika virus (ZIKV), which are 
      positive-sense, single-stranded RNA viruses replicating in the cytoplasm. The 
      KPNA6 protein level in virus-infected cells was much higher than that in 
      mock-infected controls, whereas the KPNA6 transcript remains stable. Viral 
      infection blocked the ubiquitin-proteasomal degradation of KPNA6, which led to an 
      extension of the KPNA6 half-life and the elevation of the KPNA6 level in 
      comparison to mock-infected cells. PRRSV nsp12 protein induced KPNA6 
      stabilization. KPNA6 silencing was detrimental to the replication of PRRSV, and 
      KPNA6 knockout impaired ZIKV replication. Moreover, KPNA6 knockout blocked the 
      nuclear translocation of PRRSV nsp1beta but had a minimal effect on two other PRRSV 
      proteins with nuclear localization. Exogenous restitution of KPNA6 expression in 
      the KPNA6-knockout cells results in restoration of the nuclear translocation of 
      PRRSV nsp1beta and the replication of ZIKV. These results indicate that KPNA6 is an 
      important cellular factor for the replication of PRRSV and ZIKV.IMPORTANCE 
      Positive-sense, single-stranded RNA (+ssRNA) viruses replicate in the cytoplasm 
      of infected cells. The roles of transport factors in the nucleocytoplasmic 
      trafficking system for the replication of +ssRNA viruses are not known. In this 
      study, we discovered that PRRSV and ZIKV viruses needed karyopherin alpha6 (KPNA6), 
      one of the transport factors, to enhance the virus replication. Our data showed 
      that viral infection induced an elevation of the KPNA6 protein level due to an 
      extension of the KPNA6 half-life via viral interference of the 
      ubiquitin-proteasomal degradation of KPNA6. Notably, KPNA6 silencing or knockout 
      dramatically reduced the replication of PRRSV and ZIKV. PRRSV nsp1beta depended on 
      KPNA6 to translocate into the nucleus. In addition, exogenous restitution of 
      KPNA6 expression in KPNA6-knockout cells led to the restoration of nsp1beta nuclear 
      translocation and ZIKV replication. These results reveal a new aspect in the 
      virus-cell interaction and may facilitate the development of novel antiviral 
      therapeutics.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Yang, Liping
AU  - Yang L
AD  - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland 
      Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
FAU - Wang, Rong
AU  - Wang R
AD  - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland 
      Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
FAU - Yang, Shixing
AU  - Yang S
AD  - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland 
      Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
FAU - Ma, Zexu
AU  - Ma Z
AD  - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland 
      Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
FAU - Lin, Shaoli
AU  - Lin S
AD  - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland 
      Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
FAU - Nan, Yuchen
AU  - Nan Y
AD  - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland 
      Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
FAU - Li, Qisheng
AU  - Li Q
AD  - Liver Diseases Branch, National Institute of Diabetes and Digestive Kidney 
      Diseases, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Tang, Qiyi
AU  - Tang Q
AD  - Department of Microbiology, Howard University College of Medicine, Washington, 
      DC, USA.
FAU - Zhang, Yan-Jin
AU  - Zhang YJ
AUID- ORCID: 0000-0002-5847-3260
AD  - Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland 
      Pathogen Research Institute, University of Maryland, College Park, Maryland, USA 
      zhangyj@umd.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180413
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (KPNA6 protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Viral Nonstructural Proteins)
RN  - 0 (alpha Karyopherins)
SB  - IM
MH  - Aedes
MH  - Animals
MH  - Cell Line, Tumor
MH  - Chlorocebus aethiops
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Nuclear Pore/genetics
MH  - Porcine respiratory and reproductive syndrome virus/genetics/*physiology
MH  - Protein Transport/*genetics
MH  - RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction/genetics
MH  - Swine
MH  - Vero Cells
MH  - Viral Nonstructural Proteins/*metabolism
MH  - Virus Replication/*genetics/physiology
MH  - Zika Virus/genetics/*physiology
MH  - alpha Karyopherins/*genetics
PMC - PMC5899184
OTO - NOTNLM
OT  - KPNA6
OT  - KPNA6 turnover
OT  - PRRSV
OT  - ZIKV
OT  - karyopherin alpha6
OT  - nucleocytoplasmic trafficking system
OT  - porcine reproductive and respiratory syndrome virus
OT  - virus replication
EDAT- 2018/02/16 06:00
MHDA- 2018/05/18 06:00
PMCR- 2018/10/13
CRDT- 2018/02/16 06:00
PHST- 2018/01/16 00:00 [received]
PHST- 2018/02/09 00:00 [accepted]
PHST- 2018/02/16 06:00 [pubmed]
PHST- 2018/05/18 06:00 [medline]
PHST- 2018/02/16 06:00 [entrez]
PHST- 2018/10/13 00:00 [pmc-release]
AID - JVI.00072-18 [pii]
AID - 00072-18 [pii]
AID - 10.1128/JVI.00072-18 [doi]
PST - epublish
SO  - J Virol. 2018 Apr 13;92(9):e00072-18. doi: 10.1128/JVI.00072-18. Print 2018 May 
      1.