Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 15 January 2013
Vol. 6, Issue 258, p. ec18
[DOI: 10.1126/scisignal.2003963]

EDITORS' CHOICE

Cell Biology Activation and Inactivation of Caspase-8 by Ubiquitylation

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Death receptors (DRs) are members of the family of tumor necrosis factor receptors (TNFRs) that contain a cytoplasmic death domain and stimulate the extrinsic apoptosis pathway. Binding of DRs to their extracellular ligands results in the recruitment of adaptor proteins and the initiator caspase, caspase-8, into a membrane-proximal death-inducing signaling complex (DISC), which leads to activation of the executioner caspases and apoptosis. Ubiquitylation of caspase-8 by the E3 ubiquitin ligase Cullin3 enhances its clustering and activation. Clustering and autocatalytic processing of caspase-8 releases the catalytically active products p43 and p18. Noting that mouse embryonic fibroblasts (MEFs) lacking the E3 ligase TRAF2 (TNFR-associated factor 2) exhibit enhanced apoptosis in response to TNF compared with that of wild-type MEFs, Gonzalvez et al. investigated whether TRAF2 regulated caspase-8 activity. Inhibition of the proteasome increased the sensitivity of various cultured cell lines to apoptosis induced by ligation of DRs. In the presence of a proteasomal inhibitor, lysine 48 (K48)–linked polyubiquitylated caspase-8 accumulated in cells in response to DR ligands; the p18 region of caspase-8 was ubiquitylated. DR ligation resulted in the recruitment of TRAF2 to the DISC, where it associated with caspase-8 through an interaction with the p18 region of the protein; however, the kinetics of TRAF2 recruitment were delayed compared with that of Cullin3. Knockdown of TRAF2 inhibited ligand-induced, K48-linked polyubiquitylation of the p18 region of caspase-8 and enhanced the stability of p43 and p18. In a mouse model of liver toxicity stimulated by an antibody that activates caspase-8, mice treated with TRAF2-specific small-interfering RNA (siRNA) showed accelerated lethality compared with that of antibody-treated mice exposed to a nonspecific siRNA. Together, these data suggest that through targeting caspase-8 for degradation, TRAF2 determines the threshold for activation of the extrinsic apoptosis pathway.

F. Gonzalvez, D. Lawrence, B. Yang, S. Yee, R. Pitti, S. Marsters, V. C. Pham, J.-P. Stephan, J. Lill, A. Ashkenazi, TRAF2 sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer. Mol. Cell 48, 888–899 (2012). [PubMed]

Citation: J. F. Foley, Activation and Inactivation of Caspase-8 by Ubiquitylation. Sci. Signal. 6, ec18 (2013).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882