Abstract
The CARMA1/CARD11-BCL10-MALT1 (CBM) complex bridges T and B cell antigen receptor (TCR/BCR) ligation to MALT1 protease activation and canonical nuclear factor κB (NF-κB) signaling. Using unbiased mass spectrometry, we discover multiple serine phosphorylation sites in the MALT1 C terminus after Tcell activation. Phospho-specific antibodies reveal that CBM-associated MALT1 is transiently hyper-phosphorylated upon TCR/CD28 co-stimulation. We identify a dual role for CK1α as a kinase that is essential for CBM signalosome assembly as well as MALT1 phosphorylation. Although MALT1 phosphorylation is largely dispensable for protease activity, it fosters canonical NF-κB signaling in Jurkat and murine CD4 Tcells. Moreover, constitutive MALT1 phosphorylation promotes survival of activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) cells addicted to chronic BCR signaling. Thus, MALT1 phosphorylation triggers optimal NF-κB activation in lymphocytes and survival of lymphoma cells.
Highlights
Recognition of antigens by cognate antigen receptors expressed on T and B lymphocytes represents the initial step in mounting an adaptive immune response
We discover multiple serine phosphorylation sites in the MALT1 C terminus after T cell activation
MALT1 phosphorylation is largely dispensable for protease activity, it fosters canonical nuclear factor kB (NF-kB) signaling in Jurkat and murine CD4 T cells
Summary
Recognition of antigens by cognate antigen receptors expressed on T and B lymphocytes represents the initial step in mounting an adaptive immune response. The CARMA1/ CARD11-BCL10-MALT1 (CBM) complex bridges T or B cell antigen receptor (TCR/BCR) proximal signaling to the canonical nuclear factor kB (NF-kB) pathway and c-Jun N-terminal kinase (JNK) activation (Meininger and Krappmann, 2016). MALT1 protease activity does not directly control signaling downstream of the CBM complex (Bornancin et al, 2015; Gewies et al, 2014; Jaworski et al, 2014), but cleavage of MALT1 substrates, such as A20, BCL10, CYLD, HOIL-1, RelB, Regnase-1 (MCPIP1), or Roquin1/2, has been associated with various T cell functions (Coornaert et al, 2008; Hailfinger et al, 2011; Jeltsch et al, 2014; Klein et al, 2015; Rebeaud et al, 2008; Staal et al, 2011; Uehata et al, 2013). MALT1 scaffolding and protease activities are critical for survival of B cells derived from activated B cell-type diffuse large B cell lymphomas (ABCDLBCLs) that are addicted to chronic BCR signaling or oncogenic CARD11 mutations (Ferch et al, 2009; Hailfinger et al, 2009; Ngo et al, 2006)
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