Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling
Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling
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DOI：
10.1073/pnas.1115091109
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发表时间：
2012-06-05
影响因子：
11.1
通讯作者：
Benaroch, Philippe
中科院分区：
文献类型：
--
作者：
Garcia-Cattaneo, Alejandra;Gobert, Francois-Xavier;Benaroch, Philippe
Toll样受体（TLR）3是一种内体TLR，其在被其配体双链RNA（大多数病毒的复制中间体）激活后介导针对病毒感染的免疫应答。TLR 3在体内广泛表达，并激活先天性和适应性免疫系统。然而，很少有人知道TLR 3细胞内运输和成熟的调节。在这里，我们表明，新合成的内源性TLR 3通过ER和高尔基体运输到内体，在那里它被迅速切割。TLR 3蛋白表达被其自身配体上调，导致其裂解形式的积累。与其作为转运蛋白的拟议作用一致，UNC 93 B1表达是TLR 3切割和信号传导所必需的。此外，TLR 3信号传导和切割对组织蛋白酶抑制敏感。切割发生在氨基酸252和346之间，并导致在激活时发出信号的功能性受体。缺乏N-末端345个氨基酸的截短形式的TLR 3也响应于配体活化而从酸性隔室发出信号。通过RNA干扰筛选人组织蛋白酶家族，确定组织蛋白酶B和H为TLR 3加工的关键介质。综上所述，我们的数据表明，TLR 3蛋白水解加工是其功能所必需的，并提出了一种严格控制TLR 3信号传导的机制，从而免疫。
Toll-like receptor (TLR) 3 is an endosomal TLR that mediates immune responses against viral infections upon activation by its ligand double-stranded RNA, a replication intermediate of most viruses. TLR3 is expressed widely in the body and activates both the innate and adaptive immune systems. However, little is known about how TLR3 intracellular trafficking and maturation are regulated. Here we show that newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved. TLR3 protein expression is up-regulated by its own ligand, leading to the accumulation of its cleaved form. In agreement with its proposed role as a transporter, UNC93B1 expression is required for TLR3 cleavage and signaling. Furthermore, TLR3 signaling and cleavage are sensitive to cathepsin inhibition. Cleavage occurs between aa 252 and 346, and results in a functional receptor that signals upon activation. A truncated form of TLR3 lacking the N-terminal 345 aa also signals from acidic compartments in response to ligand activation. Screening of the human cathepsin family by RNA interference identified cathepsins B and H as key mediators of TLR3 processing. Taken together, our data indicate that TLR3 proteolytic processing is essential for its function, and suggest a mechanism of tight control of TLR3 signaling and thus immunity.