MAGUK-controlled CARMA1 and BCL-10 turnover propose a new mechanism for NF-κB inactivation in lymphocytes (33.31)
| Autor: | Miguel E Moreno-Garcia, Karen Sommer, David J Rawlings |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 182:33.31-33.31 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.182.supp.33.31 |
| Popis: | In lymphocytes, the antigen receptor utilizes a unique scaffolding molecule, CARMA1, to organize an oligomerization cascade that ultimately activates NF-kappaB. Activation of CARMA1 is characterized by conformational changes that expose binding sites to downstream effectors, including BCL10. We found that CARMA1 activation induces its own turnover, and also drives the turnover of BCL10. In B and T cell lines, activated CARMA1 is post-translationally modified by K48-linked polyubiquitin chains, and its degradation is blocked by proteasome inhibitors. CARMA1 ubiquitination was enhanced in vitro by E3 ubiquitin protein ligases cIAP2 and NEDD4 (but not Cbl-b, ITCH, or beta-TrCP). The MAGUK region of CARMA1 plays a unique role in mediating these events as the SH3 and GUK domains are main ubiquitin acceptors, and deletion of a domain (HOOK) located between SH3 and GUK was sufficient to induce E3 recruitment and constitutive ubiquitination. Additionally, we show that CARMA1 promoted parallel ubiquitination and degradation of BCL10 via a TAK1-dependent mechanism. Functionally, we demonstrated that over-expression of cIAP2 reduced the CARMA1-dependent NF-kappaB activation in antigen receptor stimulated lymphocytes. We hypothesize that up-regulation of E3 ligases by NF-kappaB provides a feed-back control mechanism to shut-down NF-kappaB activation by degrading the CARMA1 scaffold and associated downstream effectors including BCL-10. This work was funded by NIH 5RO1HD37091 and 5RO3TW007322, and CRDF UKB2-2831-06. |
| Databáze: | OpenAIRE |
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