Prenylation of an interferon-gamma-induced GTP-binding protein: the human guanylate binding protein, huGBP1.
Interferons (IFN) and lipopolysaccharide (LPS) cause multiple changes in isoprenoid-modified proteins in murine macrophages, the most dramatic being the expression of a prenyl protein of 65 kDa. The guanylate binding proteins (GBPs) are IFN-inducible GTP-binding proteins of approximately 65 kDa that possess a CaaX motif at their C-terminus, indicating that they might be substrates for prenyltransferases. The human GBP1 protein, when expressed in transfected COS-1 cells, incorporates radioactivity from the isoprenoid precursor [3H]mevalonate. In addition, huGBPs expressed from the endogenous genes in IFN-gamma-treated human fibroblasts or monocytic cells were also found to be isoprenoid modified. IFN-gamma-induced huGBPs in HL-60 cells were not labeled by the specific C20 isoprenoid, [3H]geranylgeraniol, but did show decreased isoprenoid incorporation in cells treated with the farnesyl transferase inhibitor BZA-5B, indicating that huGBPs in HL-60 cells are probably modified by a C15 farnesyl rather than the more common C20 lipid. Differentiated HL-60 cells treated with IFN-gamma/LPS showed no change in the profile of constitutive isoprenylated proteins and the IFN-gamma/LPS-induced huGBPs remained prenylated. Despite being prenylated, huGBP1 in COS cells and endogenous huGBPs in HL-60 cells were primarily (approximately 85%) cytosolic. Human GBPs are thus among the select group of prenyl proteins whose synthesis is tightly regulated by a cytokine. HuGBP1 is an abundant protein whose prenylation may be vulnerable to farnesyl transferase inhibitors that are designed to prevent farnesylation of Ras proteins.
Nantais
D E
DE
Department of Biochemistry and Biophysics, Iowa State University, Ames 50011, USA.
Schwemmle
M
M
Stickney
J T
JT
Vestal
D J
DJ
Buss
J E
JE
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D019556:COS Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D018922:HL-60 Cells / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D017368:Protein Prenylation; D014162:Transfection; D014316:Tritium
C090156:BZA 5B; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D014316:Tritium; D001569:Benzodiazepines; C015367:mevalonolactone; D007371:Interferon-gamma; D019204:GTP-Binding Proteins; D008798:Mevalonic Acid