ARIH2 is essential for embryogenesis, and its hematopoietic deficiency causes lethal activation of the immune system
Amy E Lin, Gregor Ebert, Yongkai Ow, Simon P Preston, Jesse G Toe, James P Cooney, Hamish W Scott, Masato Sasaki, Samuel D Saibil, Dilan Dissanayake, Raymond H Kim, Andrew Wakeham, Annick You-Ten, Arda Shahinian, Gordon Duncan, Jennifer Silvester, Pamela S Ohashi, Tak W Mak, Marc Pellegrini
NATURE IMMUNOLOGY | NATURE PORTFOLIO | Published : 2013
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 activati..View full abstract
Awarded by National Health and Medical Research Council Australia
We thank J. Haight for animal care; A. Elia, L. Zhou and K. So and M. Macasaet for assistance with histopathology; R. Nayyar and F. Tong for flow cytometry support; M. Herold for assistance with the transduction of retroviruses, lentiviruses and short hairpin RNA; and T. Calzascia, C. Deluca, Y.J. Yang, A. Cheung, J. Woodgett, V. Stambolic and M. Minden for discussions. Supported by the Terry Fox Cancer Foundation (T.W.M. and P.S.O.), the National Cancer Institute of Canada (T.W.M. and P.S.O.), Canada Research Chairs (P.S.O.), the Cancer Research Institute (M.P.), National Health and Medical Research Council Australia (Career Development Award 637350 to M.P.), Victorian State Government Operational Infrastructure Support (M.P.), the Independent Research Institutes Infrastructure Support Scheme of the Australian Government National Health and Medical Research Council (M.P.) and the Canadian Institutes of Health Research (A.E.L.).