Lipopolysaccharide-induced NF-kappa B activation in mouse 70Z/3 pre-B lymphocytes is inhibited by mevinolin and 5'-methylthioadenosine: roles of protein isoprenylation and carboxyl methylation reactions.
We show that both the lipopolysaccharide (LPS)-induced activation of NF-kappa DNA binding and kappa gene expression are blocked by treating murine pre-B lymphocyte 70Z/3 cells with 5'-methylthioadenosine (MTA), an inhibitor of several S-adenosylmethionine-dependent methylation reactions. We further show that the LPS-induced incorporation of radioactivity from [methyl-3H]methionine into methyl ester-like linkages on a group of membrane polypeptides is also inhibited by MTA treatment, suggesting the involvement of protein methylation reactions in the LPS signal transduction pathway. We also find that NF-kappa B and kappa gene activation in LPS-treated 70Z/3 cells is blocked by mevinolin, an inhibitor that prevents protein isoprenylation. Interestingly, mevinolin-treated cells also exhibited a marked reduction in the methylation of membrane proteins. Neither MTA nor mevinolin significantly inhibited NF-kappa B activation by phorbol myristate acetate, suggesting that these agents act early in signal transduction. These results provide the first evidence that carboxyl methylated and/or isoprenylated proteins play an essential role in the LPS-signaling pathway.
Law
R E
RE
Department of Microbiology and Immunology, University of California, Los Angeles 90024.
Stimmel
J B
JB
Damore
M A
MA
Carter
C
C
Clarke
S
S
Wall
R
R
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002999:Clone Cells; D003839:Deoxyadenosines; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000187:drug effects; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008148:Lovastatin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D008745:Methylation; D016328:NF-kappa B / Q000378:metabolism*; D014176:Protein Biosynthesis; D015398:Signal Transduction; D013872:Thionucleosides / Q000494:pharmacology*; D015533:Transcriptional Activation
D003839:Deoxyadenosines; D007145:Immunoglobulin kappa-Chains; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D008148:Lovastatin; D000241:Adenosine