ArticleThe Journal of experimental medicine2013
B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A.
Article in The Journal of experimental medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 82 citations in OpenAlex.
- Structural insights into human signal peptide peptidase.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Spatial Transcriptional Dynamics of CD74⁺ B Cells in Tertiary Lymphoid Structures Drive Immune Evolution in Penile Squamous Cell Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Autophagy Differentially Influences Toll-like Receptor 9 and B Cell-Receptor-Mediated B Cell Expansion, Expression of Major Histocompatibility Class II Proteins, and Antigenic Peptide Presentation.International journal of molecular sciences · 2025Article
- Genome-Wide Identification of the SPP/SPPL Gene Family andInternational journal of molecular sciences · 2024Article
- Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains.iScience · 2023Article
- Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis.Nature communications · 2022Article
- Longitudinal Dynamics of Human B-Cell Response at the Single-Cell Level in Response to Tdap Vaccination.Vaccines · 2021Article
- Physiological functions of SPP/SPPL intramembrane proteases.Cellular and molecular life sciences : CMLS · 2020Review
- Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti-CD74 autoantibodies in human ankylosing spondylitis.European journal of immunology · 2020Article
- Mendelian susceptibility to mycobacterial disease: recent discoveries.Human genetics · 2020Review
- Signaling Functions of Intramembrane Aspartyl-Proteases.Frontiers in cardiovascular medicine · 2020Review
- HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.Biochemical and biophysical research communications · 2019Article
- Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors.ACS medicinal chemistry letters · 2019Article
- Measurement of CD74 N-terminal Fragment Accumulation in Cells Treated with SPPL2a Inhibitor.Bio-protocol · 2019Article
- Mendelian susceptibility to mycobacterial disease: 2014-2018 update.Immunology and cell biology · 2019Review
- Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.The Journal of experimental medicine · 2019Article
- The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.EMBO reports · 2019Article
- Class II MHC antigen processing in immune tolerance and inflammation.Immunogenetics · 2019Review
- Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.Nature immunology · 2018Article
- Old vaccines, new diseases: when BCG meets SPPL2a.Nature immunology · 2018Article
Corrections and comments
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Authors and funding
21 authors at 5 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.