Abstract
The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF-κB activation. While many molecular events leading to NF-κB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR-mediated NF-κB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCθ-CBM-NF-κB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCθ for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-κB activity in unstimulated cells, and inhibits NF-κB activation induced by stimulation with PMA or constitutively active PKCθ, but not by stimulation with TNFα. Interestingly, CKIP-1 does not inhibit NF-κB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-κB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCθ-CBM-NF-κB signaling.
Highlights
The NF-kB family of transcription factors plays a key regulatory role in lymphocyte activation and generation of immune response [1]
Altered expression and/or function of CBM proteins have been reported in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL) [16,37,38] and MALT lymphoma [39]
Our data suggest that it is because casein kinase-2 interacting protein-1 (CKIP-1) localizes outside of the lipid rafts and its inhibitory effect does not extend, when cells are stimulated upon CD3/CD28 and lipid rafts are accumulated
Summary
The NF-kB family of transcription factors plays a key regulatory role in lymphocyte activation and generation of immune response [1]. CD3/CD28 costimulation induces the formation of a large multicomponent complex at the contact site between T cell and the APC, termed as immunological synapse [3,4]. This contact area of T cells is highly enriched in cholesterol and glycosphingo-lipids, termed as lipid rafts, and serve as the platform for the assembly of proximal signaling components of TCR. PKCh is recruited to the immunological synapse from the cytosol upon T cell stimulation and catalytically activated [5,6]. Activated PKCh phosphorylates CARMA1 (CARD11) to induce its conformational changes which enable CARMA1 to form the complex with Bcl10-MALT1 [7,8]. The degradation of IkBs allows NF-kB to enter the nucleus and induce transcription of target genes [1]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
