Biology Reference
In-Depth Information
the cellular environment and particular adaptive mutations of the viral
RNA is important for efficient RNA replication of HCV.
There is increasing experimental evidence that shows specific inter-
actions between various cellular factors and HCV nonstructural pro-
teins and/or RNA, possibly playing roles in HCV replication and/or
translation. Several cellular proteins interacting with NS5A, such as
hVAP-33,
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growth factor receptor-bound protein 2 adaptor protein,
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transcription factor SRCAP,
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and karyopherin b3,
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have been identi-
fied. Among them, it is of interest that hVAP-33, a SNARE-like protein,
can interact with NS5B as well; NS5A binds to the C-terminus of
hVAP-33, whereas NS5B binds to the N-terminus.
98
Down-regulation
of hVAP-33, either through siRNA or expression of a truncated,
dominant negative fragment of this protein, has lead to inhibition of
HCV RNA replication, suggesting that protein-protein interactions
among NS5A, NS5B and hVAP-33 are critical for formation of HCV
RC and viral RNA replication (Fig. 1).
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Another NS5B-interacting
protein identified is a human RNA helicase, p68.
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Expression of
NS5B alone or of all the nonstructural proteins induced the redistri-
bution of endogenous p68 from the nucleus to the cytoplasm. It has
also been shown that knockdown of p68 reduces the negative-strand
synthesis of the HCV genome, suggesting that the NS5B-p68 inter-
action and the subsequent relocalization of cellular proteins may serve
to mediate HCV replication processes.
Cellular components binding to HCV RNA are also possibly
involved in viral replication. Some candidates are La autoantigen,
polyprimidine tract-binding protein (PTB), NS1-associated protein 1
(NSAP1), human heterogeneous nuclear ribonucleoprotein (hnRNP)
L,
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40S ribosomal subunit protein,
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and the gamma subunits of
human eukaryotic initiation factors 2B (EIF2B-gamma) and 2
(EIF2-gamma).
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La antigen, which is known to bind to several
-NTR of
HCV RNA and stimulate HCV IRES-mediated translation.
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PTB,
a pre-mRNA splicing factor, is also known to bind to many viral
RNAs at several different sites, such as the IRES of poliovirus
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and
hepatitis A virus.
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viral RNAs,
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has been demonstrated to bind to the 5
′
It has been shown that PTB has an ability to
