Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14596-601. doi: 10.1073/pnas.1105020108. Epub 2011 Aug 22.
The protease activity of the paracaspase Malt1 contributes to antigen receptor-mediated lymphocyte activation and lymphomagenesis. Malt1 activity is required for optimal NF-κB activation, but little is known about the responsible substrate(s). Here we report that Malt1 cleaved the NF-κB family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA- or c-Rel-containing NF-κB complexes. Overexpression of RelB inhibited expression of canonical NF-κB target genes and led to impaired survival of diffuse large B-cell lymphoma cell lines characterized by constitutive Malt1 activity. These findings identify a central role for Malt1-dependent RelB cleavage in canonical NF-κB activation and thereby provide a rationale for the targeting of Malt1 in immunomodulation and cancer treatment.
糜蛋白酶样丝氨酸蛋白酶 Malt1 的蛋白酶活性有助于抗原受体介导的淋巴细胞激活和淋巴瘤发生。Malt1 活性对于最佳 NF-κB 激活是必需的，但负责的底物知之甚少。在这里，我们报告 Malt1 在精氨酸 85 后切割 NF-κB 家族成员 RelB。RelB 切割诱导其蛋白酶体降解，并特异性控制包含 RelA 或 c-Rel 的 NF-κB 复合物的 DNA 结合。RelB 的过表达抑制了规范的 NF-κB 靶基因的表达，并导致特征为组成性 Malt1 活性的弥漫性大 B 细胞淋巴瘤细胞系的存活受损。这些发现确定了 Malt1 依赖性 RelB 切割在规范的 NF-κB 激活中的核心作用，从而为免疫调节和癌症治疗中靶向 Malt1 提供了依据。
