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Published online
doi:10.1083/jcb.200801010
The Journal of Cell Biology, Vol. 182, No. 1, 171-184
The Rockefeller University Press, 0021-9525 $30.00
© Vince et al.
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Article

TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1–TRAF2 complex to sensitize tumor cells to TNF{alpha}



James E. Vince1, Diep Chau1, Bernard Callus1, W. Wei-Lynn Wong1, Christine J. Hawkins1, Pascal Schneider2, Mark McKinlay3, Christopher A. Benetatos3, Stephen M. Condon3, Srinivas K. Chunduru3, George Yeoh4, Robert Brink5, David L. Vaux1, and John Silke1

1 Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
2 Biochemistry Department, University of Lausanne, CH-1066 Epalinges, Switzerland
3 TetraLogic Pharmaceuticals, 365 Phoenixville Pike, Malvern, PA 19355
4 Department of Biochemistry, The University of Western Australia, Crawley, 6009, Australia
5 Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia

Correspondence to John Silke: j.silke{at}latrobe.edu.au

Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor {kappa}B (NF-{kappa}B) signaling, and sensitize cells to tumor necrosis factor {alpha} (TNF{alpha}). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1–Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1–TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF-{kappa}B signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNF{alpha}-induced death occurs. TWEAK-induced loss of the cIAP1–TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNF{alpha}-induced death, whereas primary cells remain resistant. Conversely, cIAP1–TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNF{alpha} sensitization. Lysosomal degradation of cIAP1–TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells.

Abbreviations used in this paper: cIAP1, cellular inhibitor of apoptosis 1; DD, death domain; MEF, mouse embryonic fibroblast; MVB, multivesicular body; TNFRSF, TNF receptor superfamily; TRAF, Tnf receptor-associated factor; TRAIL, TNF-related apoptosis-inducing ligand; TWEAK, TNF-like weak inducer of apoptosis; VSV, vesicular stomatitis virus.

© 2008 Vince et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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