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PMID: 23179078 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

ARIH2 is essential for embryogenesis, and its hematopoietic deficiency causes lethal activation of the immune system.

Nature immunology ·Vol. 14 ·No. 1 ·2013-01-00 ·Pages 27-33

Lin AE, Ebert G, Ow Y, Preston SP, Toe JG, Cooney JP, Scott HW, Sasaki M, Saibil SD, Dissanayake D, Kim RH, Wakeham A, You-Ten A, Shahinian A, Duncan G, Silvester J, Ohashi PS, Mak TW, Pellegrini M

Abstract

The E3 ligase ARIH2 has an unusual structure and mechanism of elongating ubiquitin chains. To understand its physiological role, we generated gene-targeted mice deficient in ARIH2. ARIH2 deficiency resulted in the embryonic death of C57BL/6 mice. On a mixed genetic background, the lethality was attenuated, with some mice surviving beyond weaning and then succumbing to an aggressive multiorgan inflammatory response. We found that in dendritic cells (DCs), ARIH2 caused degradation of the inhibitor IκBβ in the nucleus, which abrogated its ability to sequester, protect and transcriptionally coactivate the transcription factor subunit p65 in the nucleus. Loss of ARIH2 caused dysregulated activation of the transcription factor NF-κB in DCs, which led to lethal activation of the immune system in ARIH2-sufficent mice reconstituted with ARIH2-deficient hematopoietic stem cells. Our data have therapeutic implications for targeting ARIH2 function.

MeSH Terms
Animals Cells, Cultured Dendritic Cells/immunology Disease Models, Animal Embryonic Development/genetics,immunology Hematopoiesis/genetics Humans Immune System/physiology Mice Mice, Inbred C57BL Mice, Knockout Molecular Targeted Therapy Multiple Organ Failure/genetics,immunology NF-kappa B/metabolism Transcriptional Activation/immunology Ubiquitin-Protein Ligases/genetics,physiology Ubiquitination/genetics,immunology
Chemicals
NF-kappa B Arih2 protein, mouse Ubiquitin-Protein Ligases
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Lin Amy E
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Ebert Gregor
Ow Yongkai
Preston Simon P
Toe Jesse G
Cooney James P
Scott Hamish W
Sasaki Masato
Saibil Samuel D
Dissanayake Dilan
Kim Raymond H
Wakeham Andrew
You-Ten Annick
Shahinian Arda
Duncan Gordon
Silvester Jennifer
Ohashi Pamela S
Mak Tak W
Pellegrini Marc
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2478
Published
2013-01-00
Epub
2012-00-25
Pages
27-33
Language
English
Region
United States
NLM ID
100941354
Subset
IM
Grants
Canadian Institutes of Health Research · Canada
External Links
PubMed source DOI: 10.1038/ni.2478 View journal details
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