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Journal of Virology, September 1999, p. 7138-7146, Vol. 73, No. 9
Institute for Virology, Johannes Gutenberg
University Mainz, 55131 Mainz, Germany
Received 29 March 1999/Accepted 21 May 1999
NS5A of the hepatitis C virus (HCV) is a highly phosphorylated
protein involved in resistance against interferon and required most
likely for replication of the viral genome. Phosphorylation of this
protein is mediated by a cellular kinase(s) generating multiple
proteins with different electrophoretic mobilities. In the case of
the genotype 1b isolate HCV-J, in addition to the basal phosphorylated
NS5A (designated pp56), a hyperphosphorylated form (pp58) was found on
coexpression of NS4A (T. Kaneko, Y. Tanji, S. Satoh, M. Hijikata,
S. Asabe, K. Kimura, and K. Shimotohno, Biochem. Biophys. Res. Commun.
205:320-326, 1994). Using a comparative analysis of two full-length
genomes of genotype 1b, competent or defective for NS5A
hyperphosphorylation, we investigated the requirements for this
NS5A modification. We found that hyperphosphorylation occurs when NS5A
is expressed as part of a continuous NS3-5A polyprotein but not when it
is expressed on its own or trans complemented with one or
several other viral proteins. Results obtained with chimeras of both
genomes show that single amino acid substitutions within NS3 that do
not affect polyprotein cleavage can enhance or reduce NS5A
hyperphosphorylation. Furthermore, mutations in the central or
carboxy-terminal NS4A domain as well as small deletions in NS4B can
also reduce or block hyperphosphorylation without affecting polyprotein
processing. These requirements most likely reflect the formation of a
highly ordered NS3-5A multisubunit complex responsible for the
differential phosphorylation of NS5A and probably also for modulation
of its biological activities.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Modulation of Hepatitis C Virus NS5A
Hyperphosphorylation by Nonstructural Proteins NS3, NS4A, and
NS4B
*
Corresponding author. Mailing address: Institute for
Virology, Johannes Gutenberg University Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. Phone: 49 6131 174451. Fax: 49 6131 395604. E-mail: bartnsch{at}mail.uni-mainz.de.
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