title: B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A.
abstract: Druggable proteins required for B lymphocyte survival and immune responses are an emerging source of new treatments for autoimmunity and lymphoid malignancy. In this study, we show that mice with an inactivating mutation in the intramembrane protease signal peptide peptidase-like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell-activating factor (BAFF). Accumulation of Sppl2a-deficient B cells was rescued by overexpression of the BAFF-induced survival protein B cell lymphoma 2 (BCL2) but not BAFF and was distinguished by low surface BAFF receptor and IgM and IgD B cell receptors. CD8-negative dendritic cells were also greatly decreased. SPPL2A deficiency blocked the proteolytic processing of CD74 MHC II invariant chain in both cell types, causing dramatic build-up of the p8 product of Cathepsin S and interfering with earlier steps in CD74 endosomal retention and processing. The findings illuminate an important role for the final step in the CD74-MHC II pathway and a new target for protease inhibitor treatment of B cell diseases.
authors.affiliation: Ramaciotti Immunization Genomics Laboratory, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2600, Australia.
authors.forename: Hannes
authors.initials: H
authors.lastname: Bergmann
authors.forename: Mehmet
authors.initials: M
authors.lastname: Yabas
authors.forename: Alanna
authors.initials: A
authors.lastname: Short
authors.forename: Lisa
authors.initials: L
authors.lastname: Miosge
authors.forename: Nadine
authors.initials: N
authors.lastname: Barthel
authors.forename: Charis E
authors.initials: CE
authors.lastname: Teh
authors.forename: Carla M
authors.initials: CM
authors.lastname: Roots
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Bull
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Jeelall
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horikawa
authors.forename: Belinda
authors.initials: B
authors.lastname: Whittle
authors.forename: Bhavani
authors.initials: B
authors.lastname: Balakishnan
authors.forename: Geoff
authors.initials: G
authors.lastname: Sjollema
authors.forename: Edward M
authors.initials: EM
authors.lastname: Bertram
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rimmer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Field
authors.forename: T Daniel
authors.initials: TD
authors.lastname: Andrews
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Anselm
authors.initials: A
authors.lastname: Enders
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001402:B-Lymphocytes / Q000502:physiology*; D016827:CD8 Antigens / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D056724:Immunity, Humoral / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D016827:CD8 Antigens; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011961:Receptors, Fc; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; C050855:immunoglobulin D receptor; C045084:invariant chain; C052617:Bcl2 protein, mouse; D016282:Aspartic Acid Endopeptidases; C568855:SPPL2a protein, mouse