Isoprenoid requirement for intracellular transport and processing of murine leukemia virus envelope protein.
Lovastatin blocks the biosynthesis of the isoprenoid precursor, mevalonate. When Friend murine erythroleukemia (MEL) cells are cultured in medium containing lovastatin, the precursor of murine leukemia virus envelope glycoprotein (gPr90env) fails to undergo proteolytic processing, which normally occurs in the Golgi complex. Consequently, newly synthesized envelope proteins are not incorporated into viral particles that are shed into the culture medium. gPr90env appears to be localized in a pre-Golgi membrane compartment, based on its enrichment in subcellular fractions containing NADPH-cytochrome c reductase activity and the sensitivity of its carbohydrate chains to digestion with endoglycosidase H. Arrest of gPr90env processing occurs at concentrations of lovastatin that are not cytostatic, and the effect of the inhibitor is prevented by addition of mevalonate to the medium. The low molecular mass GTP-binding proteins, rab1p and rab6p, which are believed to function in early steps of the exocytic pathway, are normally modified posttranslationally by geranylgeranyl isoprenoids. However, in MEL cells treated with 1 microM lovastatin, nonisoprenylated forms of these proteins accumulate in the cytosol prior to arrest of gPr90env processing. These observations suggest that lovastatin may prevent viral envelope precursors from reaching the Golgi compartment by blocking the isoprenylation of rab proteins required for ER to Golgi transport.
Overmeyer
J H
JH
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822.
Maltese
W A
WA
D000818:Animals; D002451:Cell Compartmentation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism; D015683:Gene Products, gag / Q000378:metabolism; D006596:Hexosaminidases / Q000494:pharmacology; D066298:In Vitro Techniques; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014771:Virion / Q000378:metabolism
D015683:Gene Products, gag; D011498:Protein Precursors; D014759:Viral Envelope Proteins; D008148:Lovastatin; D006596:Hexosaminidases; D019204:GTP-Binding Proteins; D008798:Mevalonic Acid