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Nat Immunol. 2015 Jan;16(1):67-74. doi: 10.1038/ni.3046. Epub 2014 Nov 24.

The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
3
Seattle Biomedical Research Institute, Seattle, WA, USA.
4
Department of Dermatology, DIAID, Experimental Allergy, Medical University of Vienna, Vienna, Austria.
5
University of Massachusetts, Worcester, MA, USA.
6
Department of Pathology, Medical University of Vienna, Vienna, Austria.
7
Department of Medicine 1, Medical University of Vienna, Vienna, Austria.
8
Department of Pathology and Immunology, Division of Clinical Pathology, University & University Hospital of Geneva, Geneva, Switzerland.
9
Department of Neuropathology, Georg-August-University Goettingen, Germany.
10
Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
#
Contributed equally

Abstract

Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that Setdb2 was the only protein lysine methyltransferase induced during infection with influenza virus. Setdb2 expression depended on signaling via type I interferons, and Setdb2 repressed expression of the gene encoding the neutrophil attractant CXCL1 and other genes that are targets of the transcription factor NF-κB. This coincided with occupancy by Setdb2 at the Cxcl1 promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone H3 Lys9 (H3K9me3). Mice with a hypomorphic gene-trap construct of Setdb2 exhibited increased infiltration of neutrophils during sterile lung inflammation and were less sensitive to bacterial superinfection after infection with influenza virus. This suggested that a Setdb2-mediated regulatory crosstalk between the type I interferons and NF-κB pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

Comment in

PMID:
25419628
PMCID:
PMC4320687
DOI:
10.1038/ni.3046
[Indexed for MEDLINE]
Free PMC Article

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