title: Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation.
abstract: We have previously reported on a unique patient in whom homozygosity for a mutation at IRF8 (IRF8(K108E)) causes a severe immunodeficiency. Laboratory evaluation revealed a highly unusual myeloid compartment, remarkable for the complete absence of CD141 and CD161 monocytes, absence of CD11c1 conventional dendritic cells (DCs) and CD11c1/CD1231 plasmacytoid DCs, and striking granulocytic hyperplasia. The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant. Sequencing RNA from the IRF8(K108E) patient's primary blood cells prior to transplant shows not only depletion of IRF8-bound and IRF8-regulated transcriptional targets, in keeping with the distorted composition of the myeloid compartment, but also a paucity of transcripts associated with activated CD41 and CD81 T lymphocytes. This suggests that T cells reared in the absence of a functional antigen-presenting compartment in IRF8(K108E) are anergic. Biochemical characterization of the IRF8(K108E) mutant in vitro shows that loss of the positively charged side chain at K108 causes loss of nuclear localization and loss of transcriptional activity, which is concomitant with decreased protein stability, increased ubiquitination, increased small ubiquitin-like modification, and enhanced proteasomal degradation. These findings provide functional insight into the molecular basis of immunodeficiency associated with loss of IRF8.
authors.affiliation: Department of Biochemistry McGill University, Montreal, QC, Canada
authors.forename: Sandra
authors.initials: S
authors.lastname: Salem
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.forename: François
authors.initials: F
authors.lastname: Lefebvre
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.forename: Muzz
authors.initials: M
authors.lastname: Haniffa
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: David
authors.initials: D
authors.lastname: Burk
authors.forename: Albert
authors.initials: A
authors.lastname: Berghuis
authors.forename: Karina M
authors.initials: KM
authors.lastname: Butler
authors.forename: Timothy Ronan
authors.initials: TR
authors.lastname: Leahy
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D019943:Amino Acid Substitution; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D036101:Cord Blood Stem Cell Transplantation; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D007223:Infant; D050835:Interferon Regulatory Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000276:immunology / Q000628:therapy; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020125:Mutation, Missense; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D012313:RNA / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D050505:Mutant Proteins; D012313:RNA; D000099185:Interferon Regulatory Factor-8