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

定义 Roqin 的免疫调节功能：预防自身免疫所必需的新型基因

• 批准号: nhmrc : 316956
• 负责人: Prof Carola Vinuesa
• 金额: $ 48.09万
• 依托单位: Australian National University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/defining-immunoregulatory-function-preventing-autoimmunity/94467
• 关键词: Defining; immunoregulatory; function; Roqin; novel

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.

狼疮是一种全身性自身免疫性疾病，具有显着的发病率和死亡率。事实上，任何器官都会受到影响，包括肾脏、大脑和血液。狼疮是免疫系统正常调节崩溃的结果。尽管狼疮明显有显着的遗传因素，但在患有这种疾病的人类中几乎没有发现致病基因。最近，我们发现了一种新基因（名为 roqin）的新突变，这种突变会导致小鼠患上狼疮。根据Roqin结构的初步研究和预测，我们怀疑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我耐受，这通常可以防止自身免疫的发展。携带 Roqin 突变的小鼠的 T 细胞出现异常，导致它们异常激活、更容易分裂并存活更长时间。过度活化的 T 细胞诱导 B 细胞增殖并分泌针对自身组织的抗体，最终导致血小板丢失、肾脏损伤、脾脏和淋巴结肿大以及过早死亡。我们现在想要精确研究 Roqin 如何导致 T 细胞异常激活。 Roqin 的蛋白质序列预测存在两个锌指结构域，这两个结构域在物种间高度保守，在调节细胞生长中发挥关键功能。其中一个锌指是一个已知具有泛素连接酶活性的 RING 结构域，已知它在淋巴细胞信号传导的负调节和耐受性的维持中发挥着至关重要的作用。已知另一个锌指结构域对于破坏细胞因子 mRNA 的稳定性非常重要，从而影响淋巴细胞之间的通讯。阐明这种新的疾病机制将有助于了解人类狼疮的病因。它还将提供有关更具体的药物疗法的线索，这些药物疗法可能比目前可用的疗法更有效且毒性更小。