Defining the immunoregulatory function of Roqin: a novel gene essential for preventing autoimmunity

狼疮是一种系统性自身免疫性疾病，具有显著的发病率和死亡率。几乎任何器官都可能受到影响，包括肾脏、大脑和血液。狼疮是免疫系统正常调节失灵的结果。虽然狼疮有明显的遗传因素，但在患有这种疾病的人身上发现的致病基因很少。最近，我们在一种新基因（名为roqin）中发现了一种新的突变，这种突变会导致小鼠狼疮。基于对罗琴基因结构的初步调查和预测，我们推测该基因可能是一个关键的免疫调节因子。具体来说，它可能参与维持免疫自身耐受性，这通常会阻止自身免疫的发展。携带Roqin突变的小鼠的T细胞异常，导致它们异常激活，更容易分裂，存活时间更长。过度活化的T细胞诱导B细胞增殖并分泌抗体对抗自身组织，最终导致血小板减少、肾脏损伤、脾脏和淋巴结肿大以及早期死亡。我们现在想要精确地研究Roqin是如何引起异常T细胞激活的。Roqin蛋白序列预测了两个锌指结构域的存在，这两个结构域在物种间高度保守，在调节细胞生长中起关键作用。锌指中的一个环结构域具有泛素连接酶活性，在淋巴细胞信号传导的负调控和耐受性的维持中起着至关重要的作用。另一个锌指结构域对于破坏细胞因子mRNA的稳定很重要，从而影响淋巴细胞之间的通讯。阐明这种疾病的新机制将有助于了解人类狼疮的病因。它还将为更具体的药物治疗提供线索，这些药物治疗可能比目前可用的药物更有效，毒性更小。

Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investigations and prediction based on the structure of Roqin, we suspect that this gene may be a key immune regulator. Specifically, it is likely to be involved in maintenance of immunological self-tolerance, which normally prevents development of autoimmunity. Mice carrying the Roqin mutation have an abnormality of their T cells, which causes them to be abnormally activated, divide more readily and survive for longer. Hyperactivated T cells induce B cells to proliferate and secrete antibodies against self-tissues that eventually lead to loss of platelets, kidney damage, enlarged spleen and lymph nodes, and early death. We now want to investigate precisely how Roqin causes abnormal T cell activation. The protein sequence of Roqin predicts the existence of two zinc finger domains that are highly conserved across species and play critical functions in regulating cell growth. One of the zinc fingers is a RING domain known to have a ubiquitin-ligase activity, which is known to play a crucial role in negative regulation of lymphocyte signalling, and maintenance of tolerance. The other zinc finger domain is known to be important for destabilizing mRNA of cytokines, thereby influencing communication between lymphocytes. Elucidation of this novel mechanism of disease will help understand the cause of human lupus. It will also provide clues about more specific drug therapies that might be more efficacious, and carry less toxicity than those currently available.