Modulation of alpha interferon anti-hepatitis C virus activity by ISG15.
ISG15 has recently been reported to possess antiviral properties against viruses, both in vivo and in vitro. Knock-down of ISG15 gene expression by small interfering RNA followed by alpha interferon (IFN-alpha) treatment in Huh-7 cells resulted in an increased phenotypic sensitivity to IFN-alpha, as determined by measuring hepatitis C virus (HCV) RNA replication inhibition in stably transfected HCV replicon cells and in cells infected with genotype 1a HCVcc (infectious HCV). This IFN-alpha-specific effect, which was not observed with IFN-gamma, correlated with an increase in expression of the IFN-alpha-inducible genes IFI6, IFITM3, OAS1 and MX1, whereas the expression of the non-IFN-alpha-inducible genes PTBP-1 and JAK1 remained unchanged. It has previously been reported that, unlike ISG15 knock-down, increased sensitivity to IFN-alpha after knock-down of USP18 occurs through the prolonged phosphorylation of STAT-1. Combination knock-down of ISG15 and USP18 resulted in a moderate increase in IFN-alpha-inducible gene expression compared with single ISG15 or USP18 knock-down. Furthermore, the phenotype of increased gene expression after ISG15 knock-down and IFN-alpha treatment was also observed in non-hepatic cell lines A549 and HeLa. Taken together, these results reveal a novel function for ISG15 in the regulation of the IFN-alpha pathway and its antiviral effect.
Chua
Pong Kian
PK
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
McCown
Matthew F
MF
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Rajyaguru
Sonal
S
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Kular
Simran
S
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Varma
Ram
R
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Symons
Julian
J
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Chiu
Sophie S
SS
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Cammack
Nick
N
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Nájera
Isabel
I
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014162:Transfection; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication
D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014452:Ubiquitins; C074034:ISG15 protein, human