Figure 2.

Toward novel ways of MALT1 activation?. ‘The path of reference’ represents the classical pathway of MALT1 activation as depicted in Figure 1. TCR, T-cell receptor; BCR, B-cell receptor; CTL-R, C-type lectin receptor. ‘The TNFRSF way…’ is based on an understanding of and questions about signaling and NF-κB activation in the context of the OX40 pathway. OX40 stimulation leads to the recruitment of TRAF proteins at the cytoplasmic tail of the receptor,¹⁰ which might enable recruitment of a CBM complex¹¹ via binding of a CARD protein to TRAF2^{(ref. 12)} or lead to recruitment of MALT1 by TRAF6, perhaps together with BCL10.^{2, 9} ‘Other paths?’ refers to pathways relying on signaling hubs able to recruit TRAF proteins, such as the IL-17R pathway via the protein, ACT1, which could potentially attract MALT1 in similar ways as proposed for the OX40 pathway. Finally, ‘the viral route’ summarizes the recent findings³ that two viral proteins, K13 and K15, from KSHV can activate MALT1 in a BCL10-dependent and likely CARD-independent manner—K13 binds to MALT1, possibly indirectly, whereas K15 does not—thus representing potential novel MALT1 activation pathways. CARD# represents CARD11 for antigen receptor (TCR/BCR) signaling; CARD9 for C-type-lectin (CTL)-receptor signaling and potentially stands for the four CARD/CARMA family proteins (CARD9, CARD10, CARD11, CARD14) or isoforms thereof, in case of the hypothesized signaling crosstalks depicted in the figure.