Cation-independent mannose 6-phosphate receptor blocks apoptosis induced by herpes simplex virus 1 mutants lacking glycoprotein D and is likely the target of antiapoptotic activity of the glycoprotein.
Herpes simplex virus 1 mutants lacking the gene encoding glycoprotein D (gD) and the gD normally present in the envelope of the virus (gD(-/-) stocks) or mutants lacking the gD gene but containing trans-induced gD in their envelopes (gD(-/+)) cause apoptosis in human SK-N-SH cells. The gD(-/-) virions are taken up by endocytosis and are degraded, whereas gD(-/+) viruses replicate but produce gD(-/-) virus. Apoptosis is blocked by delivery of the gD gene in trans. Studies designed to test several hypotheses concerning the role of gD in apoptosis revealed the following. (i) gD(-/-) and gD(-/+) stocks induce fragmentation of cellular DNA in SK-N-SH, HEp-2, HeLa, and Vero cell lines. (ii) Chloroquine blocks apoptosis induced by gD(-/-) stocks but not by gD(-/+) stocks. The drug also rescues gD(-/-) from degradation. (iii) Cells transduced with cation-independent mannose 6-phosphate receptor (CI-MPR) block apoptosis induced by either gD(-/-) or gD(-/+) virus. (iv) Expression of sequences antisense to the cloned CI-MPR gene induced apoptosis by themselves. Wild-type virus but not gD(-/-) or gD(-/+) stocks of mutant virus blocked apoptosis induced by the expression of CI-MPR antisense sequences. These results exclude the possibility that to block apoptosis, gD must interact with its HveA receptor, a member of the tumor necrosis factor alpha receptor family. Instead, the data suggest that gD blocks the influx of lysosomal enzymes into the endosomal compartment by binding to CI-MPR. This conclusion is consistent with published reports that phosphorylated gD interacts with CI-MPR.
Zhou
Guoying
G
The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois 60637, USA.
Roizman
Bernard
B
D000818:Animals; D017209:Apoptosis; D002412:Cations / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D009154:Mutation; D017527:Receptor, IGF Type 2 / Q000378:metabolism / Q000502:physiology*; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics / Q000502:physiology*
D002412:Cations; D017527:Receptor, IGF Type 2; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1