Analysis of pathophysiology of LUBAC mediated NF-kappaB activation

LUBAC泛素连接酶通过产生线性多泛素链激活NF-kappaB。之前，我们已经确定了HOIL-1L和HOIP是LUBAC的组成部分。在这项研究中，我们确定了SHARPIN是LUBAC的另一个亚基。Cpdm小鼠是一种自发突变小鼠，表现出包括慢性皮炎在内的多型表型，缺乏SHARPIN。我们发现LUBAC其他亚基的不稳定和SHARPIN的缺乏是导致cpdm小鼠表型的原因。我们还研究了LUBAC在B细胞中介导的线性多泛素化的作用，发现LUBAC的连接酶活性对于B1细胞发育和对胸腺依赖性和胸腺非依赖性ii抗原的抗体反应是必要的。

The LUBAC ubiquitin ligase activates NF-kappaB by generating linear polyubiquitin chains. Previously, we have identified HOIL-1L and HOIP as components of LUBAC. In this study, we identified SHARPIN as the other subunit of LUBAC. Cpdm mice, a spontaneous mutant mice that exhibit pleomorphic phenotypes including chronic dermatitis, lack SHARPIN. We found that destabilization of the other subunits of LUBAC and lack of SHARPIN are causative for the phenotypes of cpdm mice. We also examined the roles of LUBAC mediated linear polyubiquitination in B cells and found that LUBAC's ligase activity is necessary for B1 cell development and antibody responses to thymus-dependent and thymus-independent-II antigens.