小柯机器人

美国加州大学伯克利分校的Gregory M. Barton和Bo Liu等研究人员合作发现UNC93B1通过招募syntenin-1来抑制TLR7信号并防止自身免疫。2019年9月23日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员报道了Toll样受体（TLR）运输分子伴侣UNC93B1的新功能，其专门限制TLR7的信号传导，但不限制TLR9的信号传导，并防止小鼠中TLR7依赖性自身免疫。研究人员发现UNC93B1中的突变导致增强的TLR7信号转导也破坏了与Syntenin-1的结合，Syntenin-1是一种与外泌体生物发生有关的蛋白质。UNC93B1和TLR7都可以在外泌体中检测到，这表明UNC93B1募集Syntenin-1有助于将TLR7分类到多囊泡小体的腔内囊泡中，从而终止信号传导。Syntenin-1的结合需要UNC93B1的磷酸化，从而提供了动态调节TLR7激活和信号传导的机制。因此，UNC93B1不仅能够正确运输核酸敏感的TLR，而且还可以设置潜在自我反应性TLR7的激活阈值。

据悉，TLR家族的至少两个成员TLR7和TLR9可以分别识别自身RNA和DNA。尽管这些受体在结构和功能上相似，但它们对自身免疫性疾病（例如系统性红斑狼疮，SLE）的贡献可能截然不同。例如，TLR7和TLR9在SLE小鼠模型中具有相反的作用。这种疾病在TLR9缺陷型小鼠中加剧，但在TLR7缺陷型小鼠中减弱。目前的研究尚未解析区分TLR7和TLR9的负调控机制。

附：英文原文

Title: UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity

Author: Olivia Majer, Bo Liu, Lieselotte S. M. Kreuk, Nevan Krogan, Gregory M. Barton

Issue&Volume: 2019-09-23

Abstract: 

At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA and DNA, respectively. Despite the structural and functional similarities between these receptors, their contribution to autoimmune diseases such as systemic lupus erythematosus (SLE) can be quite different. For example, TLR7 and TLR9 have opposing effects in mouse models of SLE; disease is exacerbated in TLR9-deficient mice but attenuated in TLR7-deficient mice1. However, mechanisms of negative regulation that differentiate between TLR7 and TLR9 have not been described. Here we report a new function for the TLR trafficking chaperone UNC93B1 that specifically limits signalling of TLR7, but not TLR9, and prevents TLR7-dependent autoimmunity in mice. We find that mutations in UNC93B1 leading to enhanced TLR7 signalling also disrupt binding to syntenin-1, a protein implicated in exosome biogenesis. Both UNC93B1 and TLR7 are detectable in exosomes, suggesting that UNC93B1 recruitment of Syntenin-1 facilitates sorting of TLR7 into intralumenal vesicles of multivesicular bodies, which terminates signalling. Syntenin-1 binding requires phosphorylation of UNC93B1, providing a mechanism for dynamic regulation of TLR7 activation and signalling. Thus, UNC93B1 not only enables proper trafficking of nucleic acid-sensing TLRs but also sets the activation threshold of potentially self-reactive TLR7.

DOI: 10.1038/s41586-019-1612-6

Source: https://www.nature.com/articles/s41586-019-1612-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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