The protease activity of the paracaspase MALT1 is controlled by monoubiquitination

C Pelzer, K Cabalzar, A Wolf, M Gonzalez, G Lenz… - Nature …, 2013 - nature.com
C Pelzer, K Cabalzar, A Wolf, M Gonzalez, G Lenz, M Thome
Nature immunology, 2013nature.com
The protease activity of the paracaspase MALT1 is central to lymphocyte activation and
lymphomagenesis, but how this activity is controlled remains unknown. Here we identify a
monoubiquitination of MALT1 on Lys644 that activated the protease function of MALT1.
Monoubiquitinated MALT1 had enhanced protease activity, whereas a ubiquitination-
deficient MALT1 mutant with replacement of that lysine with arginine (MALT1 (K644R)) had
less protease activity, which correlated with impaired induction of interleukin 2 (IL-2) via the …
Abstract
The protease activity of the paracaspase MALT1 is central to lymphocyte activation and lymphomagenesis, but how this activity is controlled remains unknown. Here we identify a monoubiquitination of MALT1 on Lys644 that activated the protease function of MALT1. Monoubiquitinated MALT1 had enhanced protease activity, whereas a ubiquitination-deficient MALT1 mutant with replacement of that lysine with arginine (MALT1(K644R)) had less protease activity, which correlated with impaired induction of interleukin 2 (IL-2) via the T cell antigen receptor in activated T cells. Expression of MALT1(K644R) diminished the survival of cells derived from diffuse large B cell lymphoma of the activated B cell–like subtype (ABC DLBCL), which require constitutive protease activity of MALT1 for survival. Thus, monoubiquitination of MALT1 is essential for its catalytic activation and is therefore a potential target for the treatment of ABC-DLBCL and for immunomodulation.
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