Biozentrum, University of Basel, 4056 Basel, Switzerland.
Biozentrum, University of Basel, 4056 Basel, Switzerland.
Cell Host Microbe. 2020 Mar 11;27(3):476-485.e7. doi: 10.1016/j.chom.2020.01.015. Epub 2020 Feb 25.
Chronically infecting pathogens avoid clearance by the innate immune system by promoting premature transition from an initial pro-inflammatory response toward an anti-inflammatory tissue-repair response. STAT3, a central regulator of inflammation, controls this transition and thus is targeted by numerous chronic pathogens. Here, we show that BepD, an effector of the chronic bacterial pathogen Bartonella henselae targeted to infected host cells, establishes an exceptional pathway for canonical STAT3 activation, thereby impairing secretion of pro-inflammatory TNF-α and stimulating secretion of anti-inflammatory IL-10. Tyrosine phosphorylation of EPIYA-related motifs in BepD facilitates STAT3 binding and activation via c-Abl-dependent phosphorylation of Y. The tyrosine-phosphorylated scaffold of BepD thus represents a signaling hub for intrinsic STAT3 activation that is independent from canonical STAT3 activation via transmembrane receptor-associated Janus kinases. We anticipate that our findings on a molecular shortcut to STAT3 activation will inspire new treatment options for chronic infections and inflammatory diseases.
慢性感染病原体通过促进从初始促炎反应向抗炎组织修复反应的过早转变来逃避先天免疫系统的清除。STAT3 是炎症的中央调节剂，控制着这种转变，因此是许多慢性病原体的靶点。在这里，我们表明，慢性细菌病原体巴尔通体亨氏杆菌的效应子 BepD 为经典 STAT3 激活建立了一条特殊途径，从而损害了促炎 TNF-α的分泌，并刺激了抗炎 IL-10 的分泌。BepD 中 EPIYA 相关基序的酪氨酸磷酸化通过 c-Abl 依赖性磷酸化 Y 促进 STAT3 结合和激活。BepD 的酪氨酸磷酸化支架因此代表了内在 STAT3 激活的信号枢纽，独立于通过跨膜受体相关的 Janus 激酶的经典 STAT3 激活。我们预计，我们关于 STAT3 激活分子捷径的发现将为慢性感染和炎症性疾病的新治疗选择提供灵感。
