AIMP2 promotes TNFalpha-dependent apoptosis via ubiquitin-mediated degradation of TRAF2.
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.
Choi
Jin Woo
JW
Center for Medicinal Protein Network and Systems Biology, Department of Molecular Medicine, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Kim
Dae Gyu
DG
Park
Min Chul
MC
Um
Jung Yeon
JY
Han
Jung Min
JM
Park
Sang Gyu
SG
Choi
Eung-Chil
EC
Kim
Sunghoon
S
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
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