A20 is a negative regulator of BCL10- and CARMA3-mediated activation of NF-kappa B

Dip. Scienze Biologiche ed Ambientali, Università degli Studi del Sannio di Benevento, Via Port'Arsa 11, 82100 Benevento, Italy.
Journal of Cell Science (Impact Factor: 5.43). 05/2008; 121(Pt 8):1165-71. DOI: 10.1242/jcs.021105
Source: PubMed


The molecular complex containing CARMA proteins, BCL10 and TRAF6 has been identified recently as a key component in the signal transduction pathways that regulate activation of the nuclear factor kappaB (NF-kappaB) transcription factor. Here, we report that the inducible protein A20 negatively regulates these signaling cascades by means of its deubiquitylation activity. We show that A20 perturbs assembly of the complex containing CARMA3, BCL10 and IKKgamma/NEMO, thereby suppressing activation of NF-kappaB. Together, our results further define the molecular mechanisms that control activation of NF-kappaB and reveal a function for A20 in the regulation of CARMA and BCL10 activity in lymphoid and non-lymphoid cells.

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Available from: Ettore Varricchio,
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    • " ␬B activation pathway ( Chiu et al . , 2009 ; Skaug et al . , 2009 ) . This concept is further strengthened by the fact that deubiquitinating enzymes , which disassemble polyubiquitin chains or remove ubiquitin from a sub - strate , are clearly involved in downregulating NF - ␬B ( Harhaj and Dixit , 2011 ; Sun , 2010 ; Hymowitz and Wertz , 2010 ; Stilo et al . , 2008 ) ."
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    • "The CBM complex was shown to promote angiotensin II-dependent vascular inflammation and atherogenesis, and these effects were reported to be reduced in Bcl10-deficient mice [30]. The protein A20, also known as tumor necrosis factor alphainduced protein 3 (TNFAIP3), acts as a negative regulator of the Bcl10-CARMA interactions in both the lymphoid and nonlymphoid cells due to its effects as a ubiquitin ligase and deubiquitinase [31]. "
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    • "As for TCR signaling, the well studied A20 and CYLD thwart NF-κB at different levels [10]. CYLD targets and inhibits the ubiquitin-dependent IKKβ kinase TAK1 and therefore prevents aberrant lymphocyte activation [18,19], while A20 dampens NF-κB activity by trimming K63-ubiquitin chains attached to MALT1 [20,21]. Our study now unveils USP34 as an additional negative regulator of NF-κB in lymphocytes. "
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