Abstract #SY19-1: Regulation of NF-kB by deugiquitinases

It was thought that receptors signaled either by serving as ion channels or by altering phosphorylation-dephosphorylation events. Work in my laboratory in the mid-nineties conclusively showed that death domain-containing receptors signaled by an entirely new mechanism, specifically, adapter (FADD)-mediated recruitment and direct activation of a death protease (FLICE/caspase-8) (1,2). Subsequent studies by my own and other laboratories showed that this was a universal mechanism deployed by death receptors (3). Further study of the NF-kB inducing death receptor, TNFR1, has recently unveiled another new signaling mechanism, that we have termed \#8220;ubiquitin editing.\#8221; Ubiquitin editing is mediated by a highly conserved single polypeptide protein, termed A20, which contains both a ubiquitin hydrolase and a ubiquitin ligase domain (4). Initially, this seemed counterintuitive as it was akin to a molecule possessing both kinase and phosphatase activities -- the ultimate futile cycle! We found, however, that these seemingly contradictory activities actually act in concert to attenuate cytokine signaling. It has recently become apparent that components of a number of signaling pathways are activated by an unusual form of ubiquitin polymerization involving isopeptide linkage through K63. This is in marked contrast to the well-known degradative linkage that involves K48. We showed that the ubiquitin hydrolase domain first removes the activating K63-linked poly-ubiquitin, following which the ubiquitin ligase domain adds on degradative K48-linked poly-ubiquitin, targeting the signaling component for proteosomal destruction. Since there was no precedence for the existence of such an enzymatic system, we asked if this phenomenon of ubiquitin editing where K63 linked poly-ubiquitin is edited to a K48 linked polymer is observed in other signaling pathways. Indeed, ubiquitin editing, was found to be used by other receptors of the innate immune system to limit NF-kB signaling. Finally, the prospect of targeting DUBs as a therapeutic modality will be discussed (5). 1. Chinnaiyan AM, O\#8217;Rourke K., Tewari M, and and DixitVM. FADD, a Novel Death Domain-Containing Protein, Interacts with the Death Domain of FAS and Initiates Apoptosis. Cell1995; 81:505-12. 2. Muzio M, Chinnaiyan AM\#8943; and DixitVM. FLICE, a Novel FADD-homologous ICE/CED-3-like Protease, is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex (DISC). Cell 1996; 85:817-27. 3. Ashkenazi A. and DixitVM. Death Receptors: Signaling and Modulation. Science 1998; 281:1305-08. 4. Wertz I, O\#8217;Rourke K\#8943; and Dixit, VM. The Concerted Action of A20 De-ubiquitination and Ubiquitin Ligase Domains Downregulates NF-\#954;B Signaling. Nature 2004; 430:694-699 . 5. Kayagaki N, Phung Q, Chan S, et al. DUBA: A Deubiquitinase That Regulates Type I Interferon Production. Science2007; 318:1628-32.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY19-1.