The protease activity of the paracaspase MALT1 is controlled by monoubiquitination
The protease activity of the paracaspase MALT1 is controlled by monoubiquitination
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DOI：
10.1038/ni.2540
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发表时间：
2013-04-01
影响因子：
30.5
通讯作者：
Thome, Margot
中科院分区：
文献类型：
--
作者：
Pelzer, Christiane;Cabalzar, Katrin;Thome, Margot
副半胱天冬酶 MALT1 的蛋白酶活性对于淋巴细胞激活和淋巴瘤发生至关重要，但如何控制这种活性仍不清楚。在这里，我们鉴定了 MALT1 在 Lys644 上的单泛素化，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，而用精氨酸替换赖氨酸的泛素化缺陷型 MALT1 突变体 (MALT1(K644R)) 的蛋白酶活性较低，这与活化 T 细胞中 T 细胞抗原受体对白细胞介素 2 (IL-2) 的诱导受损相关。 MALT1 (K644R) 的表达降低了源自活化 B 细胞样亚型 (ABC DLBCL) 的弥漫性大 B 细胞淋巴瘤的细胞的存活率，这些细胞需要 MALT1 的组成型蛋白酶活性才能存活。因此，MALT1 的单泛素化对其催化激活至关重要，因此是治疗 ABC-DLBCL 和免疫调节的潜在靶点。
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.