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TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2

Abstract

Tumour necrosis factor-α (TNF-α) is a proinflammatory mediator that exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII), which initiate biological responses by interacting with adaptor and signalling proteins. Among the signalling components that associate with TNF receptors are members of the TNF-R-associated factor (TRAF) family1,2. TRAF2 is required for TNF-α-mediated activation of c-Jun N-terminal kinase (JNK), contributes to activation of NF-κB, and mediates anti-apoptotic signals3, 4. TNF-RI and TNF-RII signalling complexes also contain the anti-apoptotic (‘inhibitor of apoptosis’) molecules c-IAP1 and c-IAP2 (refs 5, 6), which also have RING domain-dependent ubiquitin protein ligase (E3) activity7. The function of IAPs in TNF-R signalling is unknown. Here we show that binding of TNF-α to TNF-RII induces ubiquitination and proteasomal degradation of TRAF2. Although c-IAP1 bound TRAF2 and TRAF1 in vitro, it ubiquitinated only TRAF2. Expression of wild-type c-IAP1, but not an E3-defective mutant, resulted in TRAF2 ubiquitination and degradation. Moreover, E3-defective c-IAP1 prevented TNF-α-induced TRAF2 degradation and inhibited apoptosis. These findings identify a physiologic role for c-IAP1 and define a mechanism by which TNF-RII-regulated ubiquitin protein ligase activity can potentiate TNF-induced apoptosis.

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Figure 1: TNF-α induces ubiquitination and proteasome-mediated degradation of TRAF2.
Figure 2: Ubiquitination of TRAFs by IAPs in vitro.
Figure 3: Ubiquitination and proteasome-mediated degradation of TRAF2 by c-IAP1 in vivo.
Figure 4: c-IAP1-mut blocks TNF-α-induced degradation of TRAF2 and delays apoptosis.
Figure 5: Simple model of TNF-R signalling and regulation by c-IAP1.

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Acknowledgements

We are grateful to A. Weissman, C. Duckett, and Z. Liu for provision of reagents and reviews of this manuscript. X.L. is a visiting fellow from Bethune International Hospital, China.

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Li, X., Yang, Y. & Ashwell, J. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416, 345–347 (2002). https://doi.org/10.1038/416345a

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