Modulierung der NF-kB-Aktivita?t in T-Zellen durch den Carmal1-Bcl10-Malt1-Komplex

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A multitude of NF-?B regulated target genes determines the fate of activated T cells, whereas activating and de-activating signals are crucial for balancing adequate T cell responses. The presented data illustrate that negative-regulatory modulation of the Carma1-Bcl10-Malt1 (CBM)-complex is of great importance for the control of NF-?B activity in T cells. Surprisingly IKK?, a kinase that so far was thought to be involved in CBM-downstream effector functions, is needed for CBM-complex formation. IKK? exhibits a dual function regulating the CBM-complex: while initially being essential for the formation of the CBMcomplex, phosphorylation of the CBM-complex component Bcl10 by IKK? shortly after the onset of T cell activation leads to a damping of signal transduction. Biochemical analysis reveal that Bcl10 phosphorylation influences the intermolecular protein affinities of the CBMcomplex components causing a remodeling of the complex with a negative-regulatory effect. Further experiments uncover that upon persistent T cell activation Bcl10 is degraded by the lysosome. Bcl10 degradation promotes the collapse of the CBM-complex and thereby interferes with ongoing signal transduction despite persistent stimulation. Considering the fact that both negative-regulatory processes affect CBM-complex activity underscores the important role of this complex in T cell signal transduction. Moreover, the presented data demonstrate that formation of a multi-component signaling complex in activated T cells facilitates versatile positive, negative and non-hierarchical regulation.