副卡斯帕酶黏膜相关淋巴组织1（MALT1）是一种蛋白酶和支架蛋白，对传播B细胞受体（BCR）信号至NF-κB至关重要。去泛素化酶圆锥瘤素（CYLD）是最近发现的MALT1靶点，可负向调节NF-κB的激活。在这里，我们表明CYLD表达低与弥漫性大B细胞淋巴瘤（DLBCL）和幔细胞淋巴瘤（MCL）患者的不良预后有关，而慢性BCR信号传播MALT1介导的裂解及因此导致的CYLD失活和快速的蛋白酶降解。WT CYLD的异位过表达或CYLD的MALT1裂解抗性突变体减少了IκBα的磷酸化，抑制了规范的NF-κB靶基因转录并削弱了BCR依赖性淋巴瘤细胞株的生长。此外，CYLD表达沉默使BCR依赖性淋巴瘤细胞株对BCR途径抑制剂（例如BTK抑制剂伊布替尼）的NF-κB信号和细胞增殖抑制变得不那么敏感，表明这些效应部分地是由CYLD介导的。总之，我们的发现确定了MALT1介导的CYLD裂解在BCR信号传播、NF-κB活化和细胞增殖中的重要作用，从而为MALT1和泛素化酶抑制剂作为DLBCL、MCL和潜在的其他B细胞恶性肿瘤的有前途的治疗药物提供了新的认识。©2023年，作者。

The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.© 2023. The Author(s).