Antigen receptor signalling activates the canonical NF-κB pathway via the CARD11/BCL10/MALT1 (CBM) signalosome involving key, yet ill-defined roles for linear ubiquitination. The paracaspase MALT1 cleaves and removes negative checkpoint proteins, amplifying lymphocyte responses in NF-κB activation and in B-cell lymphoma subtypes. To identify new human MALT1 substrates, we compare B cells from the only known living MALT1(mut/mut) patient with healthy MALT1(+/mut) family members using 10-plex Tandem Mass Tag TAILS N-terminal peptide proteomics. We identify HOIL1 of the linear ubiquitin chain assembly complex as a novel MALT1 substrate. We show linear ubiquitination at B-cell receptor microclusters and signalosomes. Late in the NF-κB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-κB activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-κB pathway-first promoting activation via the CBM--then triggering HOIL1-dependent negative-feedback termination, preventing reactivation.

中文翻译：

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准半胱天冬酶MALT1裂解HOIL1，通过LUBAC减少线性泛素化，从而抑制淋巴细胞NF-κB信号传导。

抗原受体信号传导通过CARD11 / BCL10 / MALT1（CBM）信号小体激活典型的NF-κB途径，涉及线性泛素化的关键但尚未明确定义的作用。准半胱氨酸蛋白酶MALT1裂解并去除阴性检查点蛋白，从而放大NF-κB激活和B细胞淋巴瘤亚型中的淋巴细胞反应。为了识别新的人类MALT1底物，我们使用10层串联质量标签TAILS N末端肽组蛋白质组，比较了来自唯一已知的活MALT1（mut / mut）患者和健康MALT1（+ / mut）家庭成员的B细胞。我们确定线性泛素链大会复杂的HOIL1作为新型MALT1底物。我们在B细胞受体微簇和信号小体上显示线性泛素化。在NF-κB激活周期的后期，HOIL1的切割会暂时减少线性泛素化，包括NEMO和RIP1的线性泛素化，抑制NF-κB活化并防止其再活化。通过调节线性泛素化，MALT1既是人类规范性NF-κB途径的正负多效性调节剂，首先通过CBM促进激活，然后触发HOIL1依赖性负反馈终止，从而阻止了再激活。