Pal Ravi, Maurya Vandana, Borah Supriya, Mukhopadhyay Sangita
Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad, Telangana 500039, India.
Graduate Studies, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
iScience. 2024 Sep 27;27(11):111044. doi: 10.1016/j.isci.2024.111044. eCollection 2024 Nov 15.
Crystal structure of the secretory chorismate mutase protein of (MtbCM) reveals presence of a proline rich region on its surface that serve as a recognition site for protein-protein interaction. This study shows that MtbCM upregulates IL-10 which favors by affecting PKCε-MKP-1-p38 MAPK signaling. MtbCM translocates to the Golgi-network where it interacts with AKAP9 via its SH3-binding domain to inhibit AKAP9-PKCε interaction and reducing PKCε phosphorylation. In the absence of phosphorylated PKCε, IRAK3 fails to stabilize MKP-1 resulting in higher p38 MAPK activation and IL-10 production. expressing MtbCM survived better in infected mice. Mutation in SH3-binding domain ablated MtbCM-AKAP9 interaction resulting in IL-10 production and decreased bacterial survival. This study highlights the importance of SH3-binding domain in host-pathogen interaction and a role of MtbCM in modulation of cytokine response and mycobacterial virulence in addition to its role in shikimate pathway.
结核分枝杆菌分泌型分支酸变位酶蛋白（MtbCM）的晶体结构显示，其表面存在一个富含脯氨酸的区域，该区域作为蛋白质-蛋白质相互作用的识别位点。这项研究表明，MtbCM上调白细胞介素-10（IL-10），通过影响蛋白激酶Cε（PKCε）-丝裂原活化蛋白激酶磷酸酶-1（MKP-1）-p38丝裂原活化蛋白激酶（MAPK）信号通路，从而有利于[具体情况未提及]。MtbCM易位至高尔基体网络，在那里它通过其Src同源3（SH3）结合结构域与A激酶锚定蛋白9（AKAP9）相互作用，抑制AKAP9-PKCε相互作用并减少PKCε磷酸化。在没有磷酸化PKCε的情况下，白细胞介素-1受体相关激酶3（IRAK3）无法稳定MKP-1，导致更高的p38 MAPK活化和IL-10产生。表达MtbCM的[具体对象未提及]在感染小鼠中存活得更好。SH3结合结构域的突变消除了MtbCM-AKAP9相互作用，导致IL-10产生并降低细菌存活率。这项研究突出了SH3结合结构域在宿主-病原体相互作用中的重要性，以及MtbCM除了在莽草酸途径中的作用外，在调节细胞因子反应和分枝杆菌毒力方面的作用。
