title: The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain.
abstract: B cell development requires tight regulation to allow for the generation of a diverse repertoire while preventing the development of autoreactive cells. We report, using N-ethyl-N-nitrosourea (ENU)-induced mutagenesis, the identification of a mutant mouse (chompB) with a block in early B cell development. The blockade occurs after the transitional 1 (T1) stage and leads to a decrease in mature B cell subsets and deficits in T cell-dependent antibody responses. Additionally, chompB mice have decreases in myeloid dendritic cells (DCs). The mutation was mapped to the intramembrane protease signal peptide peptidase-like 2a (Sppl2a), a gene not previously implicated in immune cell development. Proteomic analysis identified the invariant chain (CD74) as a key substrate of Sppl2a and suggests that regulated intramembrane proteolysis of CD74 by Sppl2a contributes to B cell and DC survival. Moreover, these data suggest that modulation of Sppl2a may be a useful therapeutic strategy for treatment of B cell dependent autoimmune disorders.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Beisner
authors.forename: Petra
authors.initials: P
authors.lastname: Langerak
authors.forename: Albert E
authors.initials: AE
authors.lastname: Parker
authors.forename: Carol
authors.initials: C
authors.lastname: Dahlberg
authors.forename: Francella J
authors.initials: FJ
authors.lastname: Otero
authors.forename: Sue E
authors.initials: SE
authors.lastname: Sutton
authors.forename: Laurent
authors.initials: L
authors.lastname: Poirot
authors.forename: Whitney
authors.initials: W
authors.lastname: Barnes
authors.forename: Michael A
authors.initials: MA
authors.lastname: Young
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.forename: Ursula
authors.initials: U
authors.lastname: Bodendorf
authors.forename: Bruno
authors.initials: B
authors.lastname: Martoglio
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cravatt
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooke
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology*; D002470:Cell Survival; D003713:Dendritic Cells / Q000473:pathology* / Q000502:physiology; D005038:Ethylnitrosourea / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007136:Immunoglobulins / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D008565:Membrane Proteins; C045084:invariant chain; D016282:Aspartic Acid Endopeptidases; C568855:SPPL2a protein, mouse; D005038:Ethylnitrosourea