The Proteolytic Activity of the Paracaspase MALT1 is Key in T Cell Activation

 Fabien Rebeaud et al. Nature Immunology 2008 (3):272

Speaker: Jo-Shi Lin                       Time: 14:00-15:00, May 14, 2008

Commentator: Dr. Pin Ling                 Place: Room 601

Abstract:

    Activation of the transcription factor nuclear factor (NF)-κB is essential for the normal functioning of the T lymphocyte¹. The CBM (CARMA1-Bcl10-MALT1) signalosome, which containing CARMA1, Bcl-10 and MALT1, plays an important role in T cell receptor (TCR)-induced NF-kB activation². MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), contains a caspase-like domain and has be characterized as a paracaspase. Both MALT1 and Bcl-10 involved in activating NF-κB-dependent gene expression. However, the physical and functional interaction of Bcl-10 with MALT1 and the consequent downstream signaling events are not precisely understood. In this article, the Bcl-10 breakdown product was found in anti-CD3/CD28 or PMA/Ionomycin stimulated T cell, which was CBM signalosome dependent. The cleavage site of Bcl-10 contained arginine in the carboxyl-termini, which was analogous to the arginine-specific proteolytic activity of metacaspase (paracaspase in plants).  MALT1 is an arginine-specific cysteine-dependent protease and the Bcl-10 is one of its substrates. MALT1, but not cleaved Bcl-10, is required for optimal NF-κB activation. Besides, cleavage of Bcl-10 enhanced T cell adhesion to fibronectin. In conclusion, the proteolytic activity of MALT1 is essential for the cleavage of Bcl-10 after engagement of TCR, that controls integrin-dependent T cell adhesion indirectly. These findings suggest that the proteolytic activity of MALT1 might be a target for the development of immunomodulatory drug that fight lymphoma progression.

References:

1.      R Weil et al. Deciphering the pathway from the TCR to NF-κB. Cell Death and Differentiation (2006) 13:826

2.      Margot Thome. Crama1, Bcl-10 and MALT1 in lymphocyte development and activation. Nat Rev Immunol. 2004 (4):348