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Sci. Signal., 20 March 2012
Vol. 5, Issue 216, p. ra22
[DOI: 10.1126/scisignal.2001878]


Cellular Inhibitors of Apoptosis Are Global Regulators of NF-{kappa}B and MAPK Activation by Members of the TNF Family of Receptors

Eugene Varfolomeev1, Tatiana Goncharov1, Heather Maecker2, Kerry Zobel1, László G. Kömüves3, Kurt Deshayes1, and Domagoj Vucic1*

1 Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, USA.
2 Department of Cancer Signaling and Translational Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
3 Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.

Abstract: Tumor necrosis factor (TNF) family members are essential for the development and proper functioning of the immune system. TNF receptor (TNFR) signaling is mediated through the assembly of protein signaling complexes that activate the nuclear factor {kappa}B (NF-{kappa}B) and mitogen-activated protein kinase (MAPK) pathways in a ubiquitin-dependent manner. The cellular inhibitor of apoptosis (c-IAP) proteins c-IAP1 and c-IAP2 are E3 ubiquitin ligases that are recruited to TNFR signaling complexes through their constitutive association with the adaptor protein TNFR-associated factor 2 (TRAF2). We demonstrated that c-IAP1 and c-IAP2 were required for canonical activation of NF-{kappa}B and MAPK by members of the TNFR family. c-IAPs were required for the recruitment of inhibitor of {kappa}B kinase β (IKKβ), the IKK regulatory subunit NF-{kappa}B essential modulator (NEMO), and RBCK1/Hoil1-interacting protein (HOIP) to TNFR signaling complexes and the induction of gene expression by TNF family members. In contrast, TNFRs that stimulated the noncanonical NF-{kappa}B pathway triggered translocation of c-IAPs, TRAF2, and TRAF3 from the cytosol to membrane fractions, which led to their proteasomal and lysosomal degradation. Finally, we established that signaling by B cell–activating factor receptor 3 induced the cytosolic depletion of TRAF3, which enabled noncanonical NF-{kappa}B activation. These results define c-IAP proteins as critical regulators of the activation of NF-{kappa}B and MAPK signaling pathways by members of the TNFR superfamily.

* To whom correspondence should be addressed. E-mail: domagoj{at}

Citation: E. Varfolomeev, T. Goncharov, H. Maecker, K. Zobel, L. G. Kömüves, K. Deshayes, D. Vucic, Cellular Inhibitors of Apoptosis Are Global Regulators of NF-{kappa}B and MAPK Activation by Members of the TNF Family of Receptors. Sci. Signal. 5, ra22 (2012).

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