UNC93B1 mediates differential trafficking of endosomal TLRs.
UNC93B1 mediates differential trafficking of endosomal TLRs.
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DOI：
10.7554/elife.00291
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发表时间：
2013-02-19
期刊：
影响因子：
7.7
通讯作者：
Barton GM
中科院分区：
文献类型：
--
作者：
Lee BL;Moon JE;Shu JH;Yuan L;Newman ZR;Schekman R;Barton GM
UNC 93 B1是TLR 3、TLR 7、TLR 9、TLR 11、TLR 12和TLR 13功能所需的多通道跨膜蛋白，控制TLR从内质网（ER）向内溶酶体的运输。UNC 93 B1介导这些调节作用的机制尚不清楚。在这里，我们证明，UNC 93 B1进入分泌途径，并直接控制包装的TLR进入COPII囊泡，芽从ER。与其他COPII加载因子不同，UNC 93 B1通过后高尔基体分选步骤保持与TLR相关。出乎意料的是，这些步骤在内体TLR中是不同的。TLR 9需要UNC 93 B1介导的衔接蛋白复合物2（AP-2）的募集以递送至内溶酶体，而TLR 7、TLR 11、TLR 12和TLR 13利用替代运输途径。因此，我们的研究描述了UNC 93 B1对内体TLR进行差异分选的机制，这可能解释了这些受体在某些自身免疫性疾病中所起的不同作用。DOI：http://dx.doi.org/10.7554/eLife.00291.001 Toll样受体（TLR）是负责识别与入侵病原体相关的特定分子的蛋白质，称为病原体相关分子模式。一旦检测到这些信号，TLR就会激活身体的免疫反应，从而对抗感染。TLR的一个子集识别核酸，包括DNA和RNA，使免疫系统能够对来自各种细菌和病毒的异物做出反应。然而，身体自身的一些DNA和RNA也在细胞外发现（例如，而TLR必须能够区分这些核酸和那些属于病原体的核酸，因为不能区分两者可能导致自身免疫性疾病。为了降低这种风险，TLR被隔离在细胞内被称为内体的膜结合区室中。UNC 93 B1是一种跨膜蛋白，已知其控制TLR从内质网（TLR在内质网中聚集）向核内体的移动。然而，这种蛋白控制TLR运输的确切机制尚不清楚。现在Lee等人揭示，它直接控制内质网上至少六种TLR的包装：它有助于将这些TLR装载到囊泡中，囊泡又由高尔基体处理-高尔基体是蛋白质被分选和包装到最终目的地的细胞器。令人惊讶的是，即使在高尔基体加工后，UNC 93 B1仍然与TLR相关。Lee等人还揭示了特定的内体TLR受到不同的高尔基体后运输机制的影响。为了将TLR 9递送到内体，UNC 93 B1必须募集称为AP-2的衔接蛋白，而其他TLR似乎需要UNC 93 B1的不同作用。通过定义内体TLR差异运输的基础机制，Lee等人建议我们可以学习如何操纵TLR激活的不同方面，并深入了解某些自身免疫性疾病的原因。DOI：http://dx.doi.org/10.7554/eLife.00291.002网站
UNC93B1, a multipass transmembrane protein required for TLR3, TLR7, TLR9, TLR11, TLR12, and TLR13 function, controls trafficking of TLRs from the endoplasmic reticulum (ER) to endolysosomes. The mechanisms by which UNC93B1 mediates these regulatory effects remain unclear. Here, we demonstrate that UNC93B1 enters the secretory pathway and directly controls the packaging of TLRs into COPII vesicles that bud from the ER. Unlike other COPII loading factors, UNC93B1 remains associated with the TLRs through post-Golgi sorting steps. Unexpectedly, these steps are different among endosomal TLRs. TLR9 requires UNC93B1-mediated recruitment of adaptor protein complex 2 (AP-2) for delivery to endolysosomes while TLR7, TLR11, TLR12, and TLR13 utilize alternative trafficking pathways. Thus, our study describes a mechanism for differential sorting of endosomal TLRs by UNC93B1, which may explain the distinct roles played by these receptors in certain autoimmune diseases. DOI: http://dx.doi.org/10.7554/eLife.00291.001 Toll-like receptors (TLRs) are proteins that are responsible for recognizing specific molecules associated with invading pathogens, known as pathogen-associated molecular patterns. Upon detecting these signals, TLRs activate the body's immune response, which fights the infection. A subset of TLRs recognizes nucleic acids, including DNA and RNA, enabling the immune system to respond to foreign material from a diverse range of bacteria and viruses. However, some of the body's own DNA and RNA is also found outside cells (e.g., in the bloodstream) and TLRs must be able to discriminate between these nucleic acids and those belonging to pathogens, because failure to tell the difference between the two could result in autoimmune disease. To reduce this risk, TLRs are sequestered inside the cell within membrane-bound compartments known as endosomes. UNC93B1 is a transmembrane protein that is known to control the movement of TLRs from the endoplasmic reticulum—where TLRs are assembled—to endosomes. However, the exact mechanisms by which this protein controls TLR trafficking were unclear. Now Lee et al. reveal that it directly controls the packaging of at least six TLRs at the endoplasmic reticulum: it helps to load these TLRs into vesicles, which are in turn processed by the Golgi apparatus—the organelle wherein proteins are sorted and packaged en route to their final destinations. Surprisingly, UNC93B1 remains associated with the TLRs even after Golgi processing. Lee et al. also reveal that specific endosomal TLRs are subject to distinct post-Golgi trafficking mechanisms. In order for TLR9 to be delivered to the endosome, UNC93B1 must recruit an adaptor protein called AP-2, whereas other TLRs appear to require different actions by UNC93B1. By defining the mechanisms that underlie the differential trafficking of endosomal TLRs, Lee et al. suggest that we may learn how to manipulate distinct aspects of TLR activation, and also gain insights into the causes of certain autoimmune diseases. DOI: http://dx.doi.org/10.7554/eLife.00291.002