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A Bartonella Effector Acts as Signaling Hub for Intrinsic STAT3 Activation to Trigger Anti-inflammatory Responses

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Sorg Isabel, Schmutz Christoph, Lu Yun-Yueh, Fromm Katja, Siewert Lena K., Bögli Alexandra, Strack Kathrin, Harms Alexander, Dehio Christoph,
Project Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins
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Original article (peer-reviewed)

Journal Cell Host & Microbe
Volume (Issue) 27(3)
Page(s) 476 - 485.e7
Title of proceedings Cell Host & Microbe
DOI 10.1016/j.chom.2020.01.015

Open Access

Abstract

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.
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