B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8⁻ dendritic cells require the intramembrane endopeptidase SPPL2A

Bergmann, Hannes, Yabas, Mehmet, Short, Alanna, Miosge, Lisa, Barthel, Nadine, Teh, Charis E., Roots, Carla M., Bull, Katherine R., Jeelall, Yogesh, Horikawa, Keisuke, Whittle, Belinda, Balakishnan, Bhavani, Sjollema, Geoff, Bertram, Edward M., Mackay, Fabienne, Rimmer, Andrew J., Cornall, Richard J., Field, Matthew A., Andrews, T. Daniel, Goodnow, Christopher C., and Enders, Anselm (2013) B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8⁻ dendritic cells require the intramembrane endopeptidase SPPL2A. The Journal of Experimental Medicine, 210 (1). pp. 31-40.

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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.

Item ID: 43541
Item Type: Article (Research - C1)
ISSN: 1540-9538
Additional Information:

© 2013 Bergmann et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Funders: National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID), Wellcome Trust (WT), Australian Research Council (ARC), National Health and Medical Research Council (NHMRC), Ramaciotti Foundation (RF), Medical Research Council (MRC)
Date Deposited: 07 Sep 2016 23:52
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 25%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 25%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110703 Autoimmunity @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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