Immunity：科学家找到阻止炎症的分子开关

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我们的免疫系统对于我们的身体来说非常重要，但免疫系统有时会出现过度反应从而引起慢性疾病的发生，比如风湿和过敏。最近，来自瑞典于默奥大学和哥德堡大学的研究人员发现了一个新的分子开关--MYSM1--能够抑制这种过度反应，从而避免炎症的发生。相关研究结果发表在国际学术期刊immunity上。

领导该项研究的Nelson O. Gekara指出："发现MYSM1是一个重要的里程碑事件，这可以帮助我们深入理解免疫系统的工作机制，免疫系统应答如何受到调控以及如何防止炎症性疾病如脓毒症的发生。"

当我们的机体受到细菌或病毒等病原体感染，固有免疫系统就会激活，而对于有些人来说，免疫系统会产生过度激活，引起慢性炎症疾病甚至是肿瘤的发生。而固有免疫细胞表面的模式识别受体（PRR）能够识别病原体或死细胞表面的特定分子模式，实现对固有免疫系统的激活。

研究人员发现MYSM1是位于休眠细胞细胞核内的一个分子，他们首次证明在感染或炎症阶段MYSM1会转移到细胞核外的胞浆中发生累积，并在胞浆中干扰参与激活PRR途径的信号分子的功能，进而终止炎症反应。MYSM1就像一个分子开关，能够关闭一些炎症信号途径，因此动物体内缺少MYSM1就会导致固有免疫系统的异常激活，并导致炎症疾病的发生。

该研究团队目前正在筛选能够调节MYSM1分子活性的小分子化合物，他们希望借此发现一些对抗感染以及其他炎症疾病的新治疗方法和治疗药物。


来源：生物谷

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Deubiquitinase MYSM1 Regulates Innate Immunity through Inactivation of TRAF3 and TRAF6 Complexes

Swarupa Panda, Jonas A. Nilsson, Nelson O. Gekara

Highlights
•MYSM1 inhibits PRR pathways for pro-inflammatory and type I IFN gene induction
•MYSM1 transiently accumulates in the cytoplasm upon microbial challenge
•MYSM1 interacts with and inactivates TRAF3 and TRAF6 via its SWIRM and MPN domains
•MYSM1 protects against sepsis but renders mice more susceptible to viral infection

Summary
Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response.

http://www.cell.com/immunity/abstract/S1074-7613(15)00395-7