The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain

Schneppenheim, Janna; Dressel, Ralf; Hüttl, Susann; Lüllmann‐Rauch, Renate; Engelke, Michael; Dittmann, Kai; Wienands, Jürgen; Eskelinen, Eeva‐Liisa; Hermans‐Borgmeyer, Irm; Fluhrer, Regina; Säftig, Paul; Schröder, Bernd

doi:10.1084/jem.20121069

Cited by 105 publications

(204 citation statements)

References 59 publications

(91 reference statements)

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“…Major phenotypic findings described in this study were additionally confirmed in two SPPL2a mutant mouse lines (19,20). Additional ablation of CD74 in SPPL2a 2/2 mice improved B cell maturation and function, indicating that the B cell phenotype of these mice can be mainly ascribed to the incomplete turnover of the CD74 NTF (13). In SPPL2a 2/2 B cells, the unprocessed CD74 NTF accumulates in endosomal compartments where it disturbs membrane trafficking, leading to a highly increased abundance of endosome-derived vacuoles in these cells.…”

supporting

confidence: 72%

“…Generation of SPPL2a 2/2 mice has been described previously (13). Mice used in this study were backcrossed for 10 generations on a C57BL/6N Crl background.…”

Section: Mouse Strainsmentioning

confidence: 99%

“…We recently found that clearance of the final membrane-bound N-terminal fragment (NTF) of CD74 requires activity of the GxGD-type intramembrane protease signal peptide peptidase-like (SPPL)2a (13), but not of its closely related homolog SPPL2b (14). This unique role of SPPL2a is also conserved in human B cells (15).…”

mentioning

confidence: 99%

“…In SPPL2a-deficient B cells, unprocessed CD74 NTF accumulates in significant amounts, leading to an arrest of B cell maturation at the transitional stage 1 (T1) in mice (13). Furthermore, functionality of the remaining B cells is considerably impaired with regard to Ig production.…”

mentioning

confidence: 99%

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Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

Hüttl

Kläsener

Schweizer

et al. 2015

The Journal of Immunology

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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 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−/− 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−/− 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−/− 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.

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supporting

confidence: 72%

“…Generation of SPPL2a 2/2 mice has been described previously (13). Mice used in this study were backcrossed for 10 generations on a C57BL/6N Crl background.…”

Section: Mouse Strainsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

Hüttl

Kläsener

Schweizer

et al. 2015

The Journal of Immunology

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“…This requires cathepsin S (Riese et al 1996;Driessen et al 1999;Nakagawa et al 1999;Shi et al 1999) or cathepsins L and F (Nakagawa et al 1998;Shi et al 2000), depending on the cell type. Degradation of the remaining transmembrane fragment requires the intramembrane endopeptidase SPPL2A (Beisner et al 2013;Bergmann et al 2013;Schneppenheim et al 2013). Although early studies proposed that Ii degradation is regulated and enhanced in response to DC activation (Pierre and Mellman 1998), subsequent studies proved that Ii processing is a constitutive process and not rate limiting for antigen presentation by MHCII (Villadangos et al 2001(Villadangos et al , 2005El-Sukkari et al 2003;ten Broeke et al 2010).…”

Section: Biosynthesis Of Mhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

135

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For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4 þ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane.

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Lysosomes and lysosome‐related organelles in immune responses

Watts

2022

FEBS Open Bio

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The catabolic, degradative capacity of the endo‐lysosome system is put to good use in mammalian immune responses as is their recently established status as signaling platforms. From the ‘creative destruction’ of antigenic and ‘self’ material for antigen presentation to T cells to the re‐purposing of lysosomes as toxic exocytosable lysosome‐related organelles (granules) in leukocytes such as CD8 T cells and eosinophils, endo‐lysosomes are key players in host defense. Signaled responses to some pathogen products initiate in endo‐lysosomes and these organelles are emerging as important in distinct ways in the unique immunobiology of dendritic cells. Potential self‐inflicted toxicity from lysosomal and granule proteases is countered by expression of serpin and cystatin family members.

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The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain

Abstract: The intramembrane protease SPPL2a cleaves the NTF of invariant chain (CD74), which is essential for normal trafficking of MHC class II–containing endosomes and thus for B cell development and function.

Cited by 105 publications

References 59 publications

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Lysosomes and lysosome‐related organelles in immune responses

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