Scholarlink

<p>The extraordinary prevalence of helminths is attributable to secretion of molecules that manipulate the host immune system, facilitating their survival. Among the secretory products of the murine intestinal helminth <i>Heligmosomoides polygyrus</i> are 10 mimic proteins with functional resemblance to the mammalian immunosuppressive cytokine, TGF-β, but structurally distinct with five Complement Control Protein (CCP) domains, designated TGM-1 to −10. Here we dissect the structure and function of the mimic TGM-2 and its domains. We generated eight protein truncations lacking N- or C-terminal domains, for testing through pulldowns, mass spectrometric analysis and isothermal titration calorimetry, confirming affinity for TGFBR1 (ALK5), TGFBR2, and the co-receptor CD44. We observed that domains 1–3 bind TGFBR1 and TGFBR2, while domains 4 and 5 exhibit stronger binding to the CD44 co-receptor than TGM-1. Additionally, full-length TGM-2 activates the pSMAD pathway in the MFB-F11 fibroblast cell line at concentrations as low as 1 ng/mL and induces the in vitro conversion of naïve murine CD4<sup>+</sup> T cells into Foxp3<sup>+</sup> Tregs. Both stimulatory activities diminish significantly in the absence of domains 4 and 5 that interact with CD44. In vivo, both full-length TGM-2 and truncated Domains 1–3 construct potently alleviate allergic airway inflammation in mice exposed to <i>Alternaria alternata</i> allergen.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Structural and functional analysis of the TGF-β mimic, TGM-2: an immunomodulatory helminth protein

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月18日

查看全文
  • Emmaculate Yaah Ntang,
  • Kyle T. Cunningham,
  • Shashi P. Singh,
  • Claire Ciancia,
  • Anna Sanders,
  • Sergio Lilla,
  • Ananya Mukundan,
  • Stephen M. Ghogomu,
  • Andrew P. Hinck,
  • Rick M. Maizels

摘要

The extraordinary prevalence of helminths is attributable to secretion of molecules that manipulate the host immune system, facilitating their survival. Among the secretory products of the murine intestinal helminth Heligmosomoides polygyrus are 10 mimic proteins with functional resemblance to the mammalian immunosuppressive cytokine, TGF-β, but structurally distinct with five Complement Control Protein (CCP) domains, designated TGM-1 to −10. Here we dissect the structure and function of the mimic TGM-2 and its domains. We generated eight protein truncations lacking N- or C-terminal domains, for testing through pulldowns, mass spectrometric analysis and isothermal titration calorimetry, confirming affinity for TGFBR1 (ALK5), TGFBR2, and the co-receptor CD44. We observed that domains 1–3 bind TGFBR1 and TGFBR2, while domains 4 and 5 exhibit stronger binding to the CD44 co-receptor than TGM-1. Additionally, full-length TGM-2 activates the pSMAD pathway in the MFB-F11 fibroblast cell line at concentrations as low as 1 ng/mL and induces the in vitro conversion of naïve murine CD4+ T cells into Foxp3+ Tregs. Both stimulatory activities diminish significantly in the absence of domains 4 and 5 that interact with CD44. In vivo, both full-length TGM-2 and truncated Domains 1–3 construct potently alleviate allergic airway inflammation in mice exposed to Alternaria alternata allergen.