White Stephen E, Schwartze Tristin A, Mukundan Ananya, Schoenherr Christina, Singh Shashi P, van Dinther Maarten, Cunningham Kyle T, White Madeleine P J, Campion Tiffany, Pritchard John, Hinck Cynthia S, Ten Dijke Peter, Inman Gareth, Maizels Rick M, Hinck Andrew P
bioRxiv. 2023 Dec 23:2023.12.22.573140. doi: 10.1101/2023.12.22.573140.
The murine helminth parasite expresses a family of proteins structurally related to TGF-β Mimic 1 (TGM1), a secreted five domain protein that activates the TGF-β pathway and converts naïve T lymphocytes to immunosuppressive Tregs. TGM1 signals through the TGF-β type I and type II receptors, TβRI and TβRII, with domains 1-2 and 3 binding TβRI and TβRII, respectively, and domains 4-5 binding CD44, a co-receptor abundant on T cells. TGM6 is a homologue of TGM1 that is co-expressed with TGM1, but lacks domains 1 and 2. Herein, we show that TGM6 binds TβRII through domain 3, but does not bind TβRI, or other type I or type II receptors of the TGF-β family. In TGF-β reporter assays in fibroblasts, TGM6, but not truncated TGM6 lacking domains 4 and 5, potently inhibits TGF-β- and TGM1-induced signaling, consistent with its ability to bind TβRII but not TβRI or other receptors of the TGF-β family. However, TGM6 does not bind CD44 and is unable to inhibit TGF-β and TGM1 signaling in T cells. To understand how TGM6 binds TβRII, the X-ray crystal structure of the TGM6 domain 3 bound to TβRII was determined at 1.4 Å. This showed that TGM6 domain 3 binds TβRII through an interface remarkably similar to the TGF-β:TβRII interface. These results suggest that TGM6 has adapted its domain structure and sequence to mimic TGF-β binding to TβRII and function as a potent TGF-β and TGM1 antagonist in fibroblasts. The coexpression of TGM6, along with the immunosuppressive TGMs that activate the TGF-β pathway, may prevent tissue damage caused by the parasite as it progresses through its life cycle from the intestinal lumen to submucosal tissues and back again.
鼠类蠕虫寄生虫表达了一类与转化生长因子-β模拟物1（TGM1）结构相关的蛋白质，TGM1是一种分泌型五结构域蛋白，可激活转化生长因子-β信号通路并将初始T淋巴细胞转化为免疫抑制性调节性T细胞（Tregs）。TGM1通过转化生长因子-βⅠ型和Ⅱ型受体（TβRI和TβRII）发出信号，其结构域1 - 2和结构域3分别与TβRI和TβRII结合，结构域4 - 5与CD44结合，CD44是T细胞上丰富的共受体。TGM6是TGM1的同源物，与TGM1共表达，但缺少结构域1和2。在此，我们表明TGM6通过结构域3与TβRII结合，但不与TβRI或转化生长因子-β家族的其他Ⅰ型或Ⅱ型受体结合。在成纤维细胞的转化生长因子-β报告基因检测中，TGM6而非缺少结构域4和5的截短型TGM6能有效抑制转化生长因子-β和TGM1诱导的信号传导，这与其结合TβRII但不结合TβRI或转化生长因子-β家族其他受体的能力一致。然而，TGM6不与CD44结合，并且无法在T细胞中抑制转化生长因子-β和TGM1信号传导。为了解TGM6如何与TβRII结合，测定了与TβRII结合的TGM6结构域3的X射线晶体结构，分辨率为1.4 Å。结果表明，TGM6结构域3通过一个与转化生长因子-β:TβRII界面非常相似的界面与TβRII结合。这些结果表明，TGM6已经调整了其结构域结构和序列，以模拟转化生长因子-β与TβRII的结合，并在成纤维细胞中作为一种有效的转化生长因子-β和TGM1拮抗剂发挥作用。TGM6与激活转化生长因子-β信号通路的免疫抑制性TGMs共同表达，可能在寄生虫从肠腔到黏膜下组织再返回的生命周期过程中防止组织损伤。
