Journal
NATURE IMMUNOLOGY
Volume 14, Issue 1, Pages 27-33Publisher
NATURE PORTFOLIO
DOI: 10.1038/ni.2478
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Funding
- Terry Fox Cancer Foundation
- National Cancer Institute of Canada
- Canada Research Chairs
- Cancer Research Institute
- National Health and Medical Research Council Australia [637350]
- Victorian State Government Operational Infrastructure Support
- Independent Research Institutes Infrastructure Support Scheme of the Australian Government National Health and Medical Research Council
- Canadian Institutes of Health Research
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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 I kappa B beta 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-kappa B 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.
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