Looks Like a Protease, Walks Like a Protease…

Abstract

The protein MALT1 (for mucosa-associated lymphoid tissue lymphoma translocation 1) has sequence similarity to proteases, but its best-characterized signaling role is not derived from protease activity. MALT1 is a component of the signalosome protein complex that transmits signals from the T cell and B cell antigen receptors to the transcriptional regulator NF-κB. In the signalosome, MALT1’s presumed protease activity appears not to be essential to activation of NF-κB, and MALT1 instead contributes to ubiquitination of IκB kinase γ (IKKγ). Two papers now show that the protease catalytic domain is indeed put to good use during T cell activation. Rebeaud et al . show that the adaptor protein Bcl-10 (also part of the signalosome) is a target for MALT1-mediated proteolysis. They went on to develop an inhibitor of MALT1 protease activity and showed that although NF-κB through the T cell receptor did not require MALT1 activity, the protease was necessary for optimal activation of NF-κB. Furthermore, depletion of MALT1 or Bcl-10 with siRNA showed that cleavage of Bcl-10 was required for optimal adhesion of activated T cells to fibronectin. Coornaert et al . discovered another target of MALT1-mediated proteolysis--the A20 protein, an inhibitor of NF-κB signaling pathway that they found was also recruited to the signalosome. A20 has deubiquitinase activity, and one of its targets is IKKγ. The MALT-1-mediated cleavage of A20 may inhibit deubiquitination of IKKγ by lopping off a binding domain of A20 that interacts with IKKγ. Thus, MALT1’s protease activity apparently has at least two effects on immune responses to antigen--inactivation of an inhibitor of the NF-κB signaling pathway and facilitation of integrin-mediated adhesion. McAllister-Lucas and Lucas provide background and commentary. F. Rebeaud, S. Hailfinger, A. Posevitz-Fejfar, M. Tapernoux, R. Moser, D. Rueda, O. Gaide, M. Guzzardi, E. M. Iancu, N. Rufer, N. Fasel, M. Thome, The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat. Immunol . 9 , 272-281 (2008). [PubMed] B. Coornaert, M. Baens, K. Heyninck, T. Bekaert, M. Haegman, J. Staal, L. Sun, Z. J. Chen, P. Marynen, R. Beyaert, T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20. Nat. Immunol. 9 , 263-271 (2008). [PubMed] L. M. McAllister-Lucas, P. C. Lucas, Finally, MALT1 is a protease! Nat. Immunol. 9 , 231-233 (2008). [PubMed]