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CYLD regulates TNF-mediated NF-κB signaling by controlling binding of RIP to NEMO

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • Y Zhao
  • EI Zaika
  • CA Ma
  • JJ Spinner
  • MC Kinney
  • DB Conze
  • K Iwai
  • JD Ashwell
  • EM Oltz
  • DW Ballard
  • A. Jain


Activation of the transcription factor NF-kB by TNF signaling is important for cellular survival and immunity. Biochemical analysis of TNF receptor signaling complexes has revealed that ubiquitin chains are covalently linked to RIP, and their interaction with the UBAN motif of NEMO was required for efficient NF-kB activation. We show that the NEMO zinc finger and the ubiquitin hydrolase CYLD are physiologic regulators of this process. Double mutant (DM) mice that are deficient in CYLD and harbor a point mutation in the NEMO zinc finger (K392R) are early embryonic lethal that can be rescued by the absence of TNF receptor 1 (TNFR1). TNF signaling in DM cells leads to rapid accumulation of ubiquitinated RIP in the TNFR1 signaling complex. However, the TNFR1 complex in DM is compromised because the NEMO UBAN motif in DM cells is pre-occupied with linear ubiquitin complexes that prevent NEMO from associating with ubiquitinated RIP. As a result, NF-kB activation mediated by TNF signaling is greatly attenuated in DM cells rendering them sensitive to TNF- induced death. We propose that the NEMO zinc finger and CYLD regulate the induction of NF-kB signaling by controlling the non-covalent binding of linear ubiquitin to NEMO.

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