{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:46:55Z","timestamp":1791287215920,"version":"4.1.0"},"reference-count":84,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The invariant chain (CD74), a chaperone in MHC class II\u2013mediated 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 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 SPPL2a\u2212\/\u2212 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 SPPL2a\u2212\/\u2212 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 surface IgM are not directly linked processes. In line with disturbances in PI3K\/Akt signaling, SPPL2a\u2212\/\u2212 B cells show a dysregulation 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1403171","type":"journal-article","created":{"date-parts":[[2015,7,9]],"date-time":"2015-07-09T01:56:04Z","timestamp":1436406964000},"page":"1548-1563","source":"Crossref","is-referenced-by-count":32,"title":["Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells"],"prefix":"10.1093","volume":"195","author":[{"given":"Susann","family":"H\u00fcttl","sequence":"first","affiliation":[{"name":"Biochemical Institute, Christian Albrechts University of Kiel , D-24118 Kiel ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Kl\u00e4sener","sequence":"additional","affiliation":[{"name":"BIOSS Centre for Biological Signalling Studies, University of Freiburg , D-79104 Freiburg ,","place":["Germany"]},{"name":"Institute for Biology III, Faculty of Biology, University of Freiburg , D-79104 Freiburg ,","place":["Germany"]},{"name":"Max Planck Institute for Immunobiology and Epigenetics , D-79108 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Center for Molecular Neurobiology, University Medical Center Hamburg\u2013Eppendorf , D-20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Schneppenheim","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Christian Albrechts University of Kiel , D-24118 Kiel ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Heinrich","family":"Oberg","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Christian Albrechts University of Kiel , D-24105 Kiel ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Kabelitz","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Christian Albrechts University of Kiel , D-24105 Kiel ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Reth","sequence":"additional","affiliation":[{"name":"BIOSS Centre for Biological Signalling Studies, University of Freiburg , D-79104 Freiburg ,","place":["Germany"]},{"name":"Institute for Biology III, Faculty of Biology, University of Freiburg , D-79104 Freiburg ,","place":["Germany"]},{"name":"Max Planck Institute for Immunobiology and Epigenetics , D-79108 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Saftig","sequence":"additional","affiliation":[{"name":"Biochemical Institute, Christian Albrechts University of Kiel , D-24118 Kiel ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"Biochemical Institute, Christian Albrechts University of Kiel , D-24118 Kiel ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,8,15]]},"reference":[{"key":"2025030704033593700_r1","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nri3084","article-title":"Towards a systems understanding of MHC class I and MHC class II antigen presentation","volume":"11","author":"Neefjes","year":"2011","journal-title":"Nat. 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