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 Y705. 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.

中文翻译：

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巴尔通体效应子充当内在STAT3激活触发抗炎反应的信号中枢。

慢性感染的病原体通过促进从最初的促炎反应向消炎组织修复反应的过早转变，避免了先天免疫系统的清除。STAT3是炎症的中央调节剂，它控制着这种转变，因此被许多慢性病原体作为目标。在这里，我们显示BepD（针对感染的宿主细胞的慢性细菌病原体巴尔通体（Bartonella henselae）的效应物）建立了规范STAT3激活的异常途径，从而削弱了促炎性TNF-α的分泌并刺激了抗炎性IL-的分泌。 10。BepD中EPIYA相关基元的酪氨酸磷酸化通过Y705的c-Abl依赖性磷酸化促进STAT3结合和激活。因此，BepD的酪氨酸磷酸化支架代表固有STAT3激活的信号枢纽，独立于经由跨膜受体相关的Janus激酶的经典STAT3激活。我们预期我们对STAT3激活分子捷径的发现将为慢性感染和炎症性疾病激发新的治疗选择。