A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection.
The hepatitis C virus (HCV) E2 protein has been shown to block apoptosis and has been suggested to facilitate persistent infection of the virus. Here, we report that the anti-apoptotic activity of E2 is mediated by activation of nuclear factor kappa B (NF-kappaB) that directs expression of survival gene products such as tumor necrosis factor (TNF-alpha) receptor-associated factor 2 (TRAF2), X-chromosome-linked inhibitor of apoptosis protein (XIAP), FLICE-like inhibitory protein (FLIP), and survivin. Increased levels of these proteins were observed in HCV-infected cells and a cell line producing HCV E2 protein. The activation of NF-kappaB was mediated by HCV-E2-induced expression of the molecular chaperone glucose-regulated protein 94 (GRP94). Overexpression of GRP94 alone resulted in expression of anti-apoptotic proteins and blocked apoptosis induced by tumor-necrosis-related apoptosis-inducing ligand (TRAIL). Interestingly, increased levels of GRP94 were observed in cells supporting HCV proliferation that originated from liver tissues from HCV patients. Moreover, small interfering RNA (siRNA) knock-down of GRP94 nullified the anti-apoptotic activity of HCV E2.


CONCLUSIONS
These data indicate that HCV E2 blocks apoptosis induced by HCV infection and the host immune system through overproduction of GRP94, and that HCV E2 plays an important role in persistent HCV infection.
Lee
Song Hee
SH
PBC, Department of Life Science, Pohang University of Science and Technology, Hyoja-dong, Pohang, Kyungbuk, Korea.
Song
Ran
R
Lee
Mi Nam
MN
Kim
Chon Saeng
CS
Lee
Hanna
H
Kong
Young-Yun
YY
Kim
Hoguen
H
Jang
Sung Key
SK
D000328:Adult; D000368:Aged; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008099:Liver / Q000378:metabolism / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077022:Survivin; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C053387:endoplasmin; C091015:glycoprotein E2, Hepatitis C virus