Immunity同期刊登中國學者兩項成果

來自清華大學醫學院，以及中科院生物物理研究所等處的研究人員發表題為“The Adaptor SAP Controls NK Cell Activation by Regulating the Enzymes Vav-1 and SHIP-1 and by Enhancing Conjugates with Target Cells”等兩篇文章，分別闡述了X連鎖的淋巴細胞異常增生癥相關的分子機制，以及STING蛋白結構與功能研究的新成果。

來自生物物理研究所，加州大學洛杉磯分校等處的研究人員利用X-射線晶體學，生物化學和細胞生物學技術，先后解析了STING CTD以及STING CTD與c-di-GMP二元復合物的晶體結構。

闡明了STING CTD形成功能性二聚體的分子機制，文獻報道的最后一個跨膜區（153-173aa）其實并不是跨膜區而是STING CTD形成同源二聚體的疏水相互作用界面。STING CTD與c-di-GMP以一種全新的模式結合。

研究人員認為，這一結構是第一個發表的哺乳動物來源的蛋白質與c-di-GMP形成的復合物晶體結構。此外，他們還發現c-di-GMP能促進STING與TBK1結合，誘導I型干擾素的產生，從而激發機體抵抗病原體入侵的免疫反應。

這項研究工作的完成有助于深入了解STING在天然免疫信號通路中的作用，為揭示宿主細胞感知病原菌入侵的分子機制提供了直接的結構生物學證據，同時也為設計新的環鳥苷二磷酸類似物疫苗佐劑或免疫治療藥物奠定基礎。

此外另外一篇文章則揭示了和人類免疫系統疾病-X連鎖的淋巴細胞異常增生癥（XLP disease）相關的分子機制。研究人員發現SAP分子在多種類型的免疫細胞中扮演著重要的角色，而且，他們試圖去理解為什么SAP是自然殺傷細胞的重要組分，自然殺傷細胞可以有效清除異常的血細胞。

在這項研究中，研究人員發現SAP是通過雙重的機制來激活NK細胞功能的，一方面，SAP可以偶聯必要的基因和酶來增強NK細胞的殺傷效應；另一方面，它可以抑制基因產生效應。SAP與大多數XLP病人密切相關，除此之外，這項研究也闡明了SAP在其它疾病諸如狼瘡和關節炎等中的作用。

這篇文章由清華大學醫學院董忠軍研究組與加拿大蒙特利爾臨床研究所合作完成，董忠軍研究員為第一作者和通訊作者這一。

原文摘要：

Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP Binding

STING is an essential signaling molecule for DNA and cyclic di-GMP (c-di-GMP)-mediated type I interferon (IFN) production via TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway. It contains an N-terminal transmembrane region and a cytosolic C-terminal domain (CTD). Here, we describe crystal structures of STING CTD alone and complexed with c-di-GMP in a unique binding mode. The strictly conserved aa 153173 region was shown to be cytosolic and participated in dimerization via hydrophobic interactions. The STING CTD functions as a dimer and the dimerization was independent of posttranslational modifications. Binding of c-di-GMP enhanced interaction of a shorter construct of STING CTD (residues 139344) with TBK1. This suggests an extra TBK1 binding site, other than serine 358. This study provides a glimpse into the unique architecture of STING and sheds light on the mechanism of c-di-GMP-mediated TBK1 signaling.

The Adaptor SAP Controls NK Cell Activation by Regulating the Enzymes Vav-1 and SHIP-1 and by Enhancing Conjugates with Target Cells

The adaptor SAP, mutated in X-linked lymphoproliferative disease, has critical roles in multiple immune cell types. Among these, SAP is essential for the ability of natural killer (NK) cells to eliminate abnormal hematopoietic cells. Herein, we elucidated the molecular and cellular bases of this activity. SAP enhanced NK cell responsiveness by a dual molecular mechanism. It coupled SLAM family receptors to the kinase Fyn, which triggered the exchange factor Vav-1 and augmented NK cell activation. SAP also prevented the inhibitory function of SLAM family receptors. This effect was Fyn independent and correlated with uncoupling of SLAM family receptors from the lipid phosphatase SHIP-1. Both mechanisms cooperated to enable conjugate formation with target cells and to stimulate cytotoxicity and cytokine secretion by NK cells. These data showed that SAP secures NK cell activation by a dichotomous molecular mechanism, which is required for conjugate formation. These findings may have implications for the role of SAP in other immune cell types.