CD44 acts as a coreceptor for cell-specific enhancement of signaling and regulatory T cell induction by TGM1, a parasite TGF-β mimic.
CD44 acts as a coreceptor for cell-specific enhancement of signaling and regulatory T cell induction by TGM1, a parasite TGF-β mimic.
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DOI：
10.1073/pnas.2302370120
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发表时间：
2023-08-22
影响因子：
11.1
通讯作者：
Maizels, Rick M.
中科院分区：
文献类型：
--
作者：
van Dinther, Maarten;Cunningham, Kyle T.;Singh, Shashi Prakash;White, Madeleine P. J.;Campion, Tiffany;Ciancia, Claire;van Veelen, Peter A.;de Ru, Arnoud H.;Gonzalez-Prieto, Roman;Mukundan, Ananya;Byeon, Chang- Hyeock;Staggers, Sophia R.;Hinck, Cynthia S.;Hinck, Andrew P.;ten Dijke, Peter;Maizels, Rick M.
病原体针对关键的免疫途径生存。由多脑Heligmosomoides polygyrus分泌的TGF-β模拟物（TGM 1）结合宿主TGF-β受体以触发免疫抑制途径，利用不同的结构域结合每个受体亚基。我们现在展示了TGM 1结合CD 44的其他结构域，这既最大化了它的信号传导能力，又以细胞类型特异性的方式传递了它的信号。因此，TGM 1的多个模块代表了高度进化的寄生虫选择性免疫调节的独特且有效的模式。长寿寄生虫通过高度进化的分子策略逃避宿主免疫。鼠肠道蠕虫多脑Heligmosomoides polygyrus通过释放免疫抑制性TGF-β模拟物TGM 1下调宿主免疫系统，TGM 1是CCP（Sushi）蛋白家族的不同成员。TGM 1包含5个结构域，其中结构域1-3（D1/2/3）结合哺乳动物TGF-β受体，作用于T细胞以诱导Foxp 3+调节性T细胞;然而，结构域4和5（D4/5）的作用仍然未知。我们注意到缺少D4/5的截短的TGM 1显示出降低的效力。D1/2/3和D4/5作为单独蛋白质的组合没有改变效力，表明需要物理连接，并且这些结构域不传递独立信号。用生物素化的D4/5处理的细胞的共沉淀，随后用质谱法鉴定细胞表面蛋白CD 44为TGM 1的共受体。全长和D4/5都与一系列原代细胞和细胞系强烈结合，比单独的D1/2/3结合的程度更大，尽管一些细胞系对TGM 1没有反应。异位表达的CD 44在无反应的细胞赋予的反应性，而CD 44的基因耗竭废除增强D4/5和消融全长TGM 1的能力，结合到细胞表面。此外，CD 44缺陷型T细胞显示全长TGM 1对Foxp 3的诱导减弱至与D1/2/3诱导的水平相似。因此，已知结合两种宿主细胞因子受体亚基的寄生虫蛋白已经进化出第三种受体特异性，其用于提高哺乳动物细胞中TGF-β信号传导的亲合力和细胞类型特异性效力。
Pathogens target key immune pathways for their survival. The TGF-β mimic (TGM1) secreted by Heligmosomoides polygyrus binds host TGF-β receptors to trigger immune suppressive pathways, utilizing different domains to bind each of the receptor subunits. We now show additional domains of TGM1 bind CD44, which both maximizes its signaling potency and delivers its signal in a cell type–specific manner. Thus, multiple modules of TGM1 represent a unique and effective mode of selective immune modulation by a highly evolved parasite. Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive TGF-β mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-β receptors, acting on T cells to induce Foxp3+ regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type–specific potency of TGF-β signaling in mammalian cells.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
4.4
作者：
Johnson LA;Banerji S;Lagerholm BC;Jackson DG
通讯作者：
Jackson DG
DOI：
10.1083/jcb.134.4.1075
发表时间：
1996-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Clark RA;Alon R;Springer TA
通讯作者：
Springer TA
影响因子：
3.6
作者：
Byfield, SD;Major, C;Roberts, AB
通讯作者：
Roberts, AB
影响因子：
11.2
作者：
Deckers, M;van Dinther, M;ten Dijke, P
通讯作者：
ten Dijke, P