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Published July 22, 2011 | Accepted Version
Journal Article Open

Sam68 Is Required for Both NF-κB Activation and Apoptosis Signaling by the TNF Receptor

Abstract

The RNA-binding protein Sam68 is implicated in various cellular processes including RNA metabolism, apoptosis, and signal transduction. Here we identify a role of Sam68 in TNF-induced NF-κB activation and apoptosis. We found that Sam68 is recruited to the TNF receptor, and its deficiency dramatically reduces RIP recruitment and ubiquitylation. It also impairs cIAP1 recruitment and maintenance of recruited TRAF2 at the TNF receptor. In its absence, activation of the TAK1-IKK kinase complex is defective, greatly reducing signal transduction. Sam68 is also found as a part of the TNF-induced cytoplasmic caspase-8-FADD complex. RIP is not recruited to this complex in Sam68 knockout cells, and caspase activation is virtually absent. These findings delineate previously unknown functions for Sam68 in the TNF signaling pathway, where it acts as a signaling adaptor both in the membrane-associated complex I and in the cytoplasmic complex II, regulating both NF-κB activation and apoptosis.

Additional Information

© 2011 Elsevier Inc. Received 1 December 2010; revised 14 March 2011; accepted 9 May 2011. Published online: May 26, 2011. Available online 27 May 2011. We thank Stephane Richard, McGill University, Canada, for kindly providing the Sam68 knockout and wild-type MEF cells. We thank David Shalloway for Sam68 plasmids, Chee-Kwee Ea for expression vectors for TNF and TNFR as well as advice, Shengli Hao for several qPCR primers, and members of the Baltimore laboratory and Reshmi Parameswaran for helpful discussions. P.R. is supported by the National Institutes of Health grant 2R01GM039458 to D.B.

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