AIMP2 promotes TNFα-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 TNFα-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 TNFα signaling. TNFα-induced cell death was compromised in AIMP2-deficient or -suppressed cells and exogenous supplementation of AIMP2 augmented apoptotic sensitivity to TNFα signaling. This activity was confirmed by the AIMP2-dependent increase of IκB and suppression of NFκB. We found binding of AIMP2 to TRAF2, a key player in the TNFα 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 TNFα via the downregulation of TRAF2 expression.

AIMP2 Controls Intestinal Stem Cell Compartments and Tumorigenesis by Modulating Wnt/β-Catenin Signaling

“…S3I and S3J). Blockade of Wnt ligand secretion by a porcupine inhibitor, IWP4 (32), revealed that the increased Wnt/b-catenin signaling in Aimp2 Previous studies suggested that AIMP2 is involved in ubiquitination-dependent degradation of TRAF2 and p53 (17,18) by the direct interaction. Thus, we tested whether AIMP2 modulates the Wnt/b-catenin signaling by ubiquitination of DVL1.…”

“…Coimmunoprecipitation was performed as described previously (17). The cells were lysed in protein lysis buffer (0.1% NP-40, 25 mmol/L Tris, 0.5 mmol/L EGTA, 10 mmol/L NaCl, 0.5 mmol/L MgCl 2 , 1 mmol/L EDTA, proteinase/phosphatase inhibitor cocktail).…”

“…To investigate the mechanism by which AIMP2 restricts the expansion of the ISC compartment, we first examined the target genes of known AIMP2-associated signaling pathways (16)(17)(18) such as FBP (Usp29 and Cdkn1a), NF-kB (Tnf, Gadd45b, and Ciap2), and p53 (Puma, Wip1, and Phlda3; refs. 26-28).…”

“…AIMP2 serves as a scaffolding protein for the assembly of several different ARSs into the multi-tRNA synthetase complex (11). If AIMP2 is predominantly trapped in multi-synthetase complexes, a limited amount of "free" AIMP2 is available to participate in nontranslational activities, such as interacting with FBP, p53, and TRAF2 (16)(17)(18). Thus, in Aimp2 þ/À mice, the amount of AIMP2 could be insufficient to support its noncanonical functions as a signaling modulator.…”

“…Genetic disruption of Aimp2 results in neonatal lethality by defects in lung differentiation (16). It has also been reported that AIMP2 induces apoptosis by promoting the degradation of TNF-receptor associated factor 2 (TRAF2) and the activation of p53 in response to DNA damage (17,18). Interestingly, the activity of AIMP2 seems highly sensitive to Aimp2 gene dosage, suggesting that the level of AIMP2 is important for its roles as a signaling modulator (19).…”