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Microbial recognition by GEF-H1 controls IKKε mediated activation of IRF5

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  • Yun Zhao

    (Massachusetts General Hospital, Harvard Medical School)

  • Rachid Zagani

    (Massachusetts General Hospital, Harvard Medical School)

  • Sung-Moo Park

    (Massachusetts General Hospital, Harvard Medical School)

  • Naohiro Yoshida

    (Massachusetts General Hospital, Harvard Medical School)

  • Pankaj Shah

    (Massachusetts General Hospital, Harvard Medical School)

  • Hans-Christian Reinecker

    (Massachusetts General Hospital, Harvard Medical School)

Abstract

During infection, transcription factor interferon regulatory factor 5 (IRF5) is essential for the control of host defense. Here we show that the microtubule-associated guanine nucleotide exchange factor (GEF)-H1, is required for the phosphorylation of IRF5 by microbial muramyl-dipeptides (MDP), the minimal structural motif of peptidoglycan of both Gram-positive and Gram-negative bacteria. Specifically, GEF-H1 functions in a microtubule based recognition system for microbial peptidoglycans that mediates the activation of IKKε which we identify as a new upstream IKKα/β and IRF5 kinase. The deletion of GEF-H1 or dominant-negative variants of GEF-H1 prevent activation of IKKε and phosphorylation of IRF5. The GEF-H1-IKKε-IRF5 signaling axis functions independent of NOD-like receptors and is critically required for the recognition of intracellular peptidoglycans and host defenses against Listeria monocytogenes.

Suggested Citation

  • Yun Zhao & Rachid Zagani & Sung-Moo Park & Naohiro Yoshida & Pankaj Shah & Hans-Christian Reinecker, 2019. "Microbial recognition by GEF-H1 controls IKKε mediated activation of IRF5," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09283-x
    DOI: 10.1038/s41467-019-09283-x
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    Cited by:

    1. Grigory Ryzhakov & Hannah Almuttaqi & Alastair L. Corbin & Dorothée L. Berthold & Tariq Khoyratty & Hayley L. Eames & Samuel Bullers & Claire Pearson & Zhichao Ai & Kristina Zec & Sarah Bonham & Roman, 2021. "Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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