Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
Nat Immunol. 2013 Apr;14(4):337-45. doi: 10.1038/ni.2540. Epub 2013 Feb 17.
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.
糜蛋白酶样丝氨酸蛋白酶 1（MALT1）的蛋白水解酶活性对淋巴细胞的激活和淋巴瘤的发生至关重要，但这种活性是如何被调控的仍不清楚。本研究鉴定了 MALT1 赖氨酸 644 的单泛素化，该修饰激活了 MALT1 的蛋白酶功能。单泛素化的 MALT1 具有增强的蛋白酶活性，而赖氨酸 644 突变为精氨酸（MALT1（K644R））的泛素化缺陷型突变体的蛋白酶活性降低，这与激活的 T 细胞中通过 T 细胞抗原受体诱导白细胞介素 2（IL-2）的能力受损有关。表达 MALT1（K644R）会降低源自激活 B 细胞样弥漫性大 B 细胞淋巴瘤（ABC-DLBCL）的细胞的存活率，而这些细胞的存活需要 MALT1 的持续蛋白酶活性。因此，MALT1 的单泛素化对于其催化激活是必需的，因此是治疗 ABC-DLBCL 和免疫调节的潜在靶点。
