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

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 B (NF-B) signaling, and sensitize cells to tumor necrosis factor (TNF). 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-B signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNF-induced death occurs. TWEAK-induced loss of the cIAP1–TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNF-induced death, whereas primary cells remain resistant. Conversely, cIAP1–TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNF 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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