title: AIMP2 promotes TNFalpha-dependent apoptosis via ubiquitin-mediated degradation of TRAF2.
abstract: AIMP2 (aminoacyl-tRNA synthetase interacting multifunctional protein 2; also known as JTV-1) was first identified as p38 in a macromolecular protein complex that consisted of nine different aminoacyl-tRNA synthetases and two other auxiliary factors. AIMP2 also plays pivotal roles in the regulation of cell proliferation and death. Although AIMP2 was previously shown to augment TNFalpha-induced cell death, its working mechanism in this signal pathway was not understood. Here, we investigate the functional significance and mode of action of AIMP2 in TNFalpha signaling. TNFalpha-induced cell death was compromised in AIMP2-deficient or -suppressed cells and exogenous supplementation of AIMP2 augmented apoptotic sensitivity to TNFalpha signaling. This activity was confirmed by the AIMP2-dependent increase of IkappaB and suppression of NFkappaB. We found binding of AIMP2 to TRAF2, a key player in the TNFalpha signaling pathway. AIMP2 augmented the association of an E3 ubiquitin ligase, c-IAP1, with TRAF2, causing ubiquitin-dependent degradation of TRAF2. These findings suggest that AIMP2 can mediate the pro-apoptotic activity of TNFalpha via the downregulation of TRAF2 expression.
authors: Center for Medicinal Protein Network and Systems Biology, Department of Molecular Medicine, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors: Jin Woo
authors: JW
authors: Choi
authors: Dae Gyu
authors: DG
authors: Kim
authors: Min Chul
authors: MC
authors: Park
authors: Jung Yeon
authors: JY
authors: Um
authors: Jung Min
authors: JM
authors: Han
authors: Sang Gyu
authors: SG
authors: Park
authors: Eung-Chil
authors: EC
authors: Choi
authors: Sunghoon
authors: S
authors: Kim
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C474321:aminoacyl-tRNA synthetase-associated protein p38; D044767:Ubiquitin-Protein Ligases; D000604:Amino Acyl-tRNA Synthetases