Published Ahead of Print 30 January 2013.
2013, 87(8):4214. DOI: 10.1128/JVI.00954-12.
Yi, David C. Swinney, Steven Foung and Stanley M. Lemon
Seungtaek Kim, Hisashi Ishida, Daisuke Yamane, MinKyung
Facilitates Cell Entry
Replication of Hepatitis C Virus: MKNK1
Protein Kinases in Cellular Entry and
Contrasting Roles of Mitogen-Activated
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Contrasting Roles of Mitogen-Activated Protein Kinases in Cellular
Entry and Replication of Hepatitis C Virus: MKNK1 Facilitates Cell
Seungtaek Kim,aHisashi Ishida,b* Daisuke Yamane,aMinKyung Yi,bDavid C. Swinney,c* Steven Foung,dStanley M. Lemona
Division of Infectious Diseases, Department of Medicine, and the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina, USAa; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USAb; Biochemical Pharmacology, Virology
DBA, Roche Palo Alto, Palo Alto, California, USAc; Department of Pathology, Stanford University School of Medicine, Stanford, California, USAd
inate the virus following acute infection, placing them at risk for
chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma
(for a review, see reference 1). Classified within the genus Hepaci-
virus of the family Flaviviridae, HCV is an enveloped virus with a
positive-sense, single-stranded RNA genome approximately 9.6
kb in length. A single open reading frame encodes a large precur-
sor polyprotein, which is processed into 10 proteins: core, E1, E2,
proteins are structural proteins that are present within the virion,
while the processed polyprotein segment extending from NS3 to
NS5B assembles into a replicase complex that directs synthesis of
both HCV replication mechanisms and host responses that re-
strict HCV infection have been intensively studied. Such knowl-
edge has led to the development of new direct-acting antiviral
fections and either arresting or reversing the progression of liver
disease. Despite this, major gaps remain in our understanding of
the biology of HCV.
One unanswered question that has relevance for both vaccine
development and antiviral therapy is why host responses are able
to successfully eliminate HCV in a minority of infected individu-
als while infections become persistent in others. Innate host re-
sponses to HCV seem likely to play a primary role in the early
elimination of virus, as this correlates strongly with polymor-
phisms in the interleukin-28B (IL-28B) (gamma 3 interferon
[IFN-?3]) gene (4). IFN-mediated Janus kinase signal transducer
of liver disease worldwide. Most infected persons fail to elim-
and activator of transcription (JAK-STAT) signaling results in
ing protein kinase R, 2=,5=-oligoadenylate synthetase, MxA, vi-
perin, interferon-stimulated gene 21, and others (5). Other cellu-
lar signaling pathways also have been shown to suppress HCV
replication, including those triggered by protein kinase C (6),
phosphoinositide-3 (PI3) kinase (7, 8), SMAD (9), extracellular
signal-regulated kinase (ERK) (7, 10, 11), and p38 kinase (12).
Although there is limited understanding of how intracellular
serine/threonine kinases involved in signal transduction that
modulate gene transcription in response to changes in extracellu-
lar stimuli (13). They control numerous fundamental cellular
processes, including proliferation, differentiation, migration, and
Received 18 April 2012 Accepted 24 January 2013
Published ahead of print 30 January 2013
Address correspondence to Stanley M. Lemon, email@example.com.
*Present address: Hisashi Ishida, Department of Gastroenterology and
Hepatology, National Hospital Organization, Osaka National Hospital, Houenzaka,
Chuo-ku, Osaka City, Osaka, Japan; David C. Swinney, Institute for Rare and
Neglected Diseases Drug Discovery, Belmont, California, USA.
S.K. and H.I. contributed equally to this work.
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
jvi.asm.orgJournal of Virologyp. 4214–4224April 2013 Volume 87 Number 8
on June 12, 2014 by guest
nases involved in HCV entry, and apparently it excluded any role
for MKNK2 (30). These authors subsequently focused on kinases
for which specific inhibitors have been approved for clinical use
and demonstrated that the epidermal growth factor receptor
(EGFR) and ephrin receptor A2 (EphA2), both receptor tyrosine
kinases, act as host factors in HCV entry. EGFR activation ap-
peared to enhance a late step in HCV entry by facilitating interac-
tions between the virus coreceptors CD81 and CLDN1. Exactly
how this happens, and what events occur downstream of the re-
ceptor tyrosine kinases, is not clear. Brazzoli et al. (31) demon-
that this mediates actin-dependent relocalization of CD81-E2
complexes toward the tight junction. This was shown to occur in
association with Raf/MEK(MAP2K)/ERK signaling, which could
and MEK-2, inhibited HCV infection, and MEK signaling ap-
Based on these prior studies, it is possible that MKNK1 is acti-
receptor tyrosine kinases during HCV entry. While MKNK1 is
inhibition of MKNK1 activity on HCV infection suggests that it
plays a significant role in this process, at least in the Huh-7 hepa-
toma cells we studied. At the same time, it is clear that each of the
3 MAPKs, ERK, p38, and JNK (as shown here), exert strong neg-
ative effects on HCV RNA replication. These contrasting effects
that there must be exquisite dynamic regulation of their activities
both temporally and spatially during the infection process.
We thank Charles Rice for Huh-7.5 cells, Craig Cameron for NS5A anti-
body, Takaji Wakita for reagents related to pseudotyped viruses, and
Lemon laboratory members for helpful comments and suggestions.
This study was supported in part by grants from the National Insti-
tutes of Health (RO1-DA024565, RO1-AI095690, and P20-CA150343).
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