Protein methyltransferase 2 inhibits NF-kappaB function and promotes apoptosis.
The protein arginine methyltransferases (PRMTs) include a family of proteins with related putative methyltransferase domains that modify chromatin and regulate cellular transcription. Although some family members, PRMT1 and PRMT4, have been implicated in transcriptional modulation or intracellular signaling, the roles of other PRMTs in diverse cellular processes have not been fully established. Here, we report that PRMT2 inhibits NF-kappaB-dependent transcription and promotes apoptosis. PRMT2 exerted this effect by blocking nuclear export of IkappaB-alpha through a leptomycin-sensitive pathway, increasing nuclear IkappaB-alpha and decreasing NF-kappaB DNA binding. The highly conserved S-adenosylmethionine-binding domain of PRMT2 mediated this effect. PRMT2 also rendered cells susceptible to apoptosis by cytokines or cytotoxic drugs, likely due to its effects on NF-kappaB. Mouse embryo fibroblasts from PRMT2 genetic knockouts showed elevated NF-kappaB activity and decreased susceptibility to apoptosis compared to wild-type or complemented cells. Taken together, these data suggest that PRMT2 inhibits cell activation and promotes programmed cell death through this NF-kappaB-dependent mechanism.
Ganesh
Lakshmanan
L
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, 40 Convent Dr., Bethesda, Maryland 20892-3005, USA.
Yoshimoto
Takanobu
T
Moorthy
Narayani C
NC
Akahata
Wataru
W
Boehm
Manfred
M
Nabel
Elizabeth G
EG
Nabel
Gary J
GJ
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D017353:Gene Deletion; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000235:genetics; D011233:Precipitin Tests; D011497:Protein O-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D005456:Fluorescent Dyes; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D011497:Protein O-Methyltransferase; D005982:Glutathione Transferase; D016650:Fluorescein-5-isothiocyanate; D000409:Alanine