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.
副胱天蛋白酶黏膜相关淋巴组织转运蛋白1（MALT1）是一种兼具蛋白酶与支架蛋白功能的分子，在将B细胞受体（BCR）信号传导至NF-κB的过程中起关键作用。去泛素化酶圆柱瘤蛋白（CYLD）是近期发现的MALT1靶点，可负向调控NF-κB活化。本研究发现，CYLD低表达与弥漫性大B细胞淋巴瘤（DLBCL）及套细胞淋巴瘤（MCL）患者不良预后相关；慢性BCR信号会促使MALT1介导的CYLD切割，进而导致CYLD失活并发生快速蛋白酶体降解。异位过表达野生型CYLD或MALT1切割抵抗型CYLD突变体，可降低IκBα磷酸化水平，抑制经典NF-κB靶基因转录，并阻碍BCR依赖性淋巴瘤细胞系的生长。此外，沉默CYLD表达会使BCR依赖性淋巴瘤细胞系对BCR通路抑制剂（如BTK抑制剂伊布替尼）抑制NF-κB信号传导及细胞增殖的敏感性降低，表明这些效应部分由CYLD介导。综上所述，我们的研究揭示了MALT1介导的CYLD切割在BCR信号传导、NF-κB活化及细胞增殖中的重要作用，为解析MALT1与泛素化酶抑制剂的分子机制及临床潜力提供了新视角，这类抑制剂有望成为DLBCL、MCL及其他B细胞恶性肿瘤的潜在治疗策略。
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