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

Yun Zhao, Rachid Zagani, Sung-Moo Park, Naohiro Yoshida, Pankaj Shah and Hans-Christian Reinecker ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09283-x

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