State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
Shanghai Engineering Research Center of Marine Cultured Animal Vaccines, Shanghai, China.
Infect Immun. 2018 Dec 19;87(1). doi: 10.1128/IAI.00508-18. Print 2019 Jan.
Bacterial phosphothreonine lyases have been identified to be type III secretion system (T3SS) effectors that irreversibly dephosphorylate host mitogen-activated protein kinase (MAPK) signaling to promote infection. However, the effects of phosphothreonine lyase on nuclear factor κB (NF-κB) signaling remain largely unknown. In this study, we detected significant phosphothreonine lyase-dependent p65 degradation during infection in macrophages, and this degradative effect was blocked by the protease inhibitor MG132. Further analysis revealed that phosphothreonine lyase promotes the dephosphorylation and ubiquitination of p65 by inhibiting the phosphorylation of mitogen- and stress-activated protein kinase-1 (MSK1) and by inhibiting the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), p38α, and c-Jun N-terminal kinase (JNK). Moreover, we revealed that the catalytic active site of phosphothreonine lyase plays a critical role in regulating the MAPK-MSK1-p65 signaling axis. Collectively, the mechanism described here expands our understanding of the pathogenic effector in not only regulating MAPK signaling but also regulating p65. These findings uncover a new mechanism by which pathogenic bacteria overcome host innate immunity to promote pathogenesis.
细菌磷酸苏氨酸裂解酶已被鉴定为 III 型分泌系统 (T3SS) 效应物，可不可逆地下调宿主丝裂原活化蛋白激酶 (MAPK) 信号转导，从而促进感染。然而，磷酸苏氨酸裂解酶对核因子 κB (NF-κB) 信号转导的影响在很大程度上仍不清楚。在本研究中，我们在巨噬细胞中检测到感染过程中磷酸苏氨酸裂解酶依赖性的 p65 降解，这种降解作用被蛋白酶抑制剂 MG132 所阻断。进一步分析表明，磷酸苏氨酸裂解酶通过抑制丝裂原和应激激活蛋白激酶 1 (MSK1) 的磷酸化以及抑制细胞外信号相关激酶 1/2 (ERK1/2)、p38α 和 c-Jun N 端激酶 (JNK) 的磷酸化，促进 p65 的去磷酸化和泛素化。此外，我们揭示了磷酸苏氨酸裂解酶的催化活性位点在调节 MAPK-MSK1-p65 信号轴中起着关键作用。综上所述，这里描述的机制扩展了我们对不仅调节 MAPK 信号转导而且调节 p65 的致病效应物的理解。这些发现揭示了一种新的机制，即致病菌通过该机制克服宿主先天免疫以促进发病机制。
