title: ARIH2 is essential for embryogenesis, and its hematopoietic deficiency causes lethal activation of the immune system.
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.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lin
authors.forename: Gregor
authors.initials: G
authors.lastname: Ebert
authors.forename: Yongkai
authors.initials: Y
authors.lastname: Ow
authors.forename: Simon P
authors.initials: SP
authors.lastname: Preston
authors.forename: Jesse G
authors.initials: JG
authors.lastname: Toe
authors.forename: James P
authors.initials: JP
authors.lastname: Cooney
authors.forename: Hamish W
authors.initials: HW
authors.lastname: Scott
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Saibil
authors.forename: Dilan
authors.initials: D
authors.lastname: Dissanayake
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Kim
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Annick
authors.initials: A
authors.lastname: You-Ten
authors.forename: Arda
authors.initials: A
authors.lastname: Shahinian
authors.forename: Gordon
authors.initials: G
authors.lastname: Duncan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Silvester
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics / Q000276:immunology*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007107:Immune System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology
chemical_list: D016328:NF-kappa B; C506697:Arih2 protein, mouse; D044767:Ubiquitin-Protein Ligases