Intestinal Epithelial Cell-Intrinsic Deletion of Setd7 Identifies Role for Developmental Pathways in Immunity to Helminth Infection.
The intestine is a common site for a variety of pathogenic infections. Helminth infections continue to be major causes of disease worldwide, and are a significant burden on health care systems. Lysine methyltransferases are part of a family of novel attractive targets for drug discovery. SETD7 is a member of the Suppressor of variegation 3-9-Enhancer of zeste-Trithorax (SET) domain-containing family of lysine methyltransferases, and has been shown to methylate and alter the function of a wide variety of proteins in vitro. A few of these putative methylation targets have been shown to be important in resistance against pathogens. We therefore sought to study the role of SETD7 during parasitic infections. We find that Setd7-/- mice display increased resistance to infection with the helminth Trichuris muris but not Heligmosomoides polygyrus bakeri. Resistance to T. muris relies on an appropriate type 2 immune response that in turn prompts intestinal epithelial cells (IECs) to alter differentiation and proliferation kinetics. Here we show that SETD7 does not affect immune cell responses during infection. Instead, we found that IEC-specific deletion of Setd7 renders mice resistant to T. muris by controlling IEC turnover, an important aspect of anti-helminth immune responses. We further show that SETD7 controls IEC turnover by modulating developmental signaling pathways such as Hippo/YAP and Wnt/β-Catenin. We show that the Hippo pathway specifically is relevant during T. muris infection as verteporfin (a YAP inhibitor) treated mice became susceptible to T. muris. We conclude that SETD7 plays an important role in IEC biology during infection.
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Menno J
MJ
Oudhoff
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Frann
F
Antignano
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Alistair L
AL
Chenery
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Kyle
0000-0001-5371-3512
K
Burrows
Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Stephen A
SA
Redpath
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Mitchell J
MJ
Braam
Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Georgia
G
Perona-Wright
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.|Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Colby
0000-0002-9889-9848
C
Zaph
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D060467:Disease Resistance; D004847:Epithelial Cells / Q000469:parasitology / Q000502:physiology; D017353:Gene Deletion; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007422:Intestines / Q000276:immunology* / Q000469:parasitology / Q000502:physiology; D051379:Mice; D009928:Organ Specificity; D010750:Phosphoproteins / Q000378:metabolism; D011166:Porphyrins / Q000009:adverse effects; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014257:Trichuriasis / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D014258:Trichuris / Q000276:immunology*; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D016207:Cytokines; D010750:Phosphoproteins; D011166:Porphyrins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin; D000077362:Verteporfin; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C562044:Setd7 protein, mouse