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Receptor Signaling in Transitional B Cells Protease Sppl2a Is Critical

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Receptor Signaling in Transitional B Cells Protease Sppl2a Is Critical Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells This information is current as Susann Hüttl, Kathrin Kläsener, Michaela Schweizer, Janna of September 25, 2021. Schneppenheim, Hans-Heinrich Oberg, Dieter Kabelitz, Michael Reth, Paul Saftig and Bernd Schröder J Immunol 2015; 195:1548-1563; Prepublished online 8 July 2015; doi: 10.4049/jimmunol.1403171 Downloaded from http://www.jimmunol.org/content/195/4/1548 Supplementary http://www.jimmunol.org/content/suppl/2015/07/08/jimmunol.140317 Material 1.DCSupplemental http://www.jimmunol.org/ References This article cites 84 articles, 43 of which you can access for free at: http://www.jimmunol.org/content/195/4/1548.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells Susann Huttl,*€ Kathrin Kla¨sener,†,‡,x Michaela Schweizer,{ Janna Schneppenheim,‖ Hans-Heinrich Oberg,# Dieter Kabelitz,# Michael Reth,†,‡,x Paul Saftig,* and Bernd Schro¨der* The invariant chain (CD74), a chaperone in MHC class II–mediated Ag presentation, is sequentially processed by different endosomal proteases. We reported recently that clearance of the final membrane-bound N-terminal fragment (NTF) of CD74 is mediated by the intramembrane protease signal peptide peptidase-like (SPPL)2a, a process critical for B cell development. In mice, SPPL2a deficiency provokes the accumulation of this NTF in endocytic vesicles, which leads to a B cell maturation arrest at Downloaded from the transitional 1 stage. To define the underlying mechanism, we analyzed the impact of SPPL2a deficiency on signaling pathways involved in B cell homeostasis. We demonstrate that tonic as well as BCR-induced activation of the PI3K/Akt pathway is massively compromised in SPPL2a2/2 B cells and identify this as major cause of the B cell maturation defect in these mice. Altered BCR trafficking induces a reduction of surface IgM in SPPL2a-deficient B cells, leading to a diminished signal transmission via the BCR and the tyrosine kinase Syk. We provide evidence that in SPPL2a2/2 mice impaired BCR signaling is to a great extent provoked by the accumulating CD74 NTF, which can interact with the BCR and Syk, and that impaired PI3K/Akt signaling and reduced http://www.jimmunol.org/ surface IgM are not directly linked processes. In line with disturbances in PI3K/Akt signaling, SPPL2a2/2 B cells show a dysreg- ulation of the transcription factor FOXO1, causing elevated transcription of proapoptotic genes. We conclude that SPPL2a- mediated processing of CD74 NTF is indispensable to maintain appropriate levels of tonic BCR signaling to promote B cell maturation. The Journal of Immunology, 2015, 195: 1548–1563. he invariant chain (CD74) is an essential component of MHCII. Interference with this process, for example by the absence the MHC class II (MHCII) Ag presentation pathway fa- of the cysteine protease cathepsin S, significantly impairs Ag T cilitating assembly and endosomal targeting of the MHCII presentation by MHCII (1). Beyond its canonical function as by guest on September 25, 2021 complexes (1). CD74 binds to the MHCII peptide-binding groove chaperone of MHCII, CD74 was reported to modulate endocytic with its CLIP segment and prevents premature peptide binding. In trafficking and endosomal maturation in APCs (2–4). Further- Ag-processing compartments, the luminal domain of CD74 is more, the regulation of dendritic cell migration (5) and also the sequentially degraded by endosomal proteases, thereby releasing cellular responses to the proinflammatory cytokine macrophage migration inhibitory factor are dependent on CD74 as cell surface receptor (6). Coreceptors such as CD44 (7) or CXCR4 (8) are *Biochemical Institute, Christian Albrechts University of Kiel, D-24118 Kiel, required to initiate signal transduction following migration in- Germany; †BIOSS Centre for Biological Signalling Studies, University of Freiburg, hibitory factor binding to CD74. Interestingly, enhanced expres- D-79104 Freiburg, Germany; ‡Institute for Biology III, Faculty of Biology, University x sion levels of CD74 have been observed in different forms of of Freiburg, D-79104 Freiburg, Germany; Max Planck Institute for Immunobiology and Epigenetics, D-79108 Freiburg, Germany; {Center for Molecular Neurobiology, malignancies and are positively correlated with increased cellular ‖ University Medical Center Hamburg–Eppendorf, D-20246 Hamburg, Germany; In- migration and/or invasion (9–11). In this context, overexpression stitute of Anatomy, Christian Albrechts University of Kiel, D-24118 Kiel, Germany; and #Institute of Immunology, Christian Albrechts University of Kiel, D-24105 Kiel, of CD74 in HEK293 cells activates central signaling pathways Germany such as the PI3K/Akt and the MAPK/ERK cascades (12). Received for publication December 22, 2014. Accepted for publication June 9, 2015. We recently found that clearance of the final membrane-bound This work was supported by the Deutsche Forschungsgemeinschaft as part of Grant N-terminal fragment (NTF) of CD74 requires activity of the SFB877 (Project B7, to B.S.) and the Cluster of Excellence “Inflammation at Inter- GxGD-type intramembrane protease signal peptide peptidase-like faces” as well as by Deutsche Forschungsgemeinschaft Grant SCHR 1284/1-1. This (SPPL)2a (13), but not of its closely related homolog SPPL2b work was also supported by the Excellence Initiative of the German Federal and State Governments (Grant EXC 294), European Research Council Grant 32297, and by (14). This unique role of SPPL2a is also conserved in human Deutsche Forschungsgemeinschaft Grants SFB746 and TRR130. B cells (15). SPPL2a is part of the SPP/SPPL protease family with Address correspondence and reprint requests to Dr. Bernd Schro¨der, Biochemical specificity for transmembrane proteins in type II orientation (16). Institute, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, D-24118 Kiel, Within this family, SPPL2a is unique with its localization in Germany. E-mail address: [email protected] lysosomes/late endosomes (14, 17). Additional substrates of SPPL2a The online version of this article contains supplemental material. include TNF-a, Fas ligand, Bri2, and TMEM106B (16, 18). Abbreviations used in this article: EEF2, eukaryotic elongation factor 2; MFI, median fluorescence intensity; MHCII, MHC class II; NTF, N-terminal fragment; PFA, para- In SPPL2a-deficient B cells, unprocessed CD74 NTF accumu- formaldehyde; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PLA, proximity liga- lates in significant amounts, leading to an arrest of B cell matu- tion assay; qRT-PCR, quantitative real-time PCR; SPP, signal peptide peptidase; ration at the transitional stage 1 (T1) in mice (13). Furthermore, SPPL, signal peptide peptidase-like; T1, transitional stage 1. functionality of the remaining B cells is considerably impaired Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 with regard to Ig production. Major phenotypic findings described www.jimmunol.org/cgi/doi/10.4049/jimmunol.1403171 The Journal of Immunology 1549 in this study were additionally confirmed in two SPPL2a mutant 100 U/ml penicillin, and 100 mg/ml streptomycin in the presence of 5 ng/ml mouse lines (19, 20). Additional ablation of CD74 in SPPL2a2/2 IL-7 (BioLegend) for 4 d as described in Rowland et al. (22). Prior to further mice improved B cell maturation and function, indicating that analysis of signaling pathways, cells were washed twice in PBS and cultured overnight in fresh complete IMDM without IL-7. the B cell phenotype of these mice can be mainly ascribed to 2 2 the incomplete turnover of the CD74 NTF (13). In SPPL2a / BCR stimulation B cells, the unprocessed CD74 NTF accumulates in endosomal Activation of the BCR was achieved by incubating the cells in the presence compartments where it disturbs membrane trafficking, leading to of 10 mg/ml goat anti-mouse IgG/IgM F(ab9)2 (Dianova). For analysis of a highly increased abundance of endosome-derived vacuoles in signal transduction pathways, cells were stimulated in 500 ml RPMI 1640 these cells. Hence, control of CD74 NTF levels by the intra- medium (Sigma-Aldrich) or 500 ml PBS for 5 min at 37˚C followed by membrane protease SPPL2a is essential for B cell maturation and Western blot or flow cytometric determination, respectively, of kinase activation (Syk, ERK1/2, Akt). Depending on the applied readout system, survival as well as the integrity of the endocytic system. In light of stimulation experiments were either performed with purified
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