Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells

Schneppenheim, Janna; Hüttl, Susann; Kruchen, Anne; Fluhrer, Regina; Müller, Ingo; Säftig, Paul; Schneppenheim, Reinhard; Martin, Christa Lese; Schröder, Bernd

doi:10.1016/j.bbrc.2014.07.051

Cited by 20 publications

(23 citation statements)

References 19 publications

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“…We could confirm recently that the essential role of SPPL2a for turnover of the CD74 NTF is preserved in human B cells (15). However, so far the functional consequences of SPPL2a deficiency on human B cell development and functionality are not known.…”

Section: Discussionsupporting

confidence: 60%

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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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Section: Discussionsupporting

confidence: 60%

“…This unique role of SPPL2a is also conserved in human B cells (15). SPPL2a is part of the SPP/SPPL protease family with specificity for transmembrane proteins in type II orientation (16).…”

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confidence: 87%

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 process resembles the way in which the intra-membrane proteases presenillin and signal peptidase act on their substrates [30]. The protease in charge of cleaving NTF within the membrane has recently been identified as a member of the signal peptidase family and has been termed signal peptide peptidase-like 2a (SPPL-2a) [98,99,100,101]. Unlike signal peptidase, SPPL-2a is located in late endosomes and lysosomes suggesting that the intramembrane cleavage of Ii-NTF may play a role in the final catabolism of Ii.…”

Section: Mif-induced Signaling From Invariant Chain Complexesmentioning

confidence: 99%

“…Unlike signal peptidase, SPPL-2a is located in late endosomes and lysosomes suggesting that the intramembrane cleavage of Ii-NTF may play a role in the final catabolism of Ii. Studies based on SPPL-2a-deficient mice, which are not able to process NTF to ICD, have revealed a severe defect in B-cell development [98,99,100,101]. This defect was accompanied by reduced BAFF-R surface expression, altered B-cell receptor (BCR) trafficking and reduced tonic BCR signaling.…”

Section: Mif-induced Signaling From Invariant Chain Complexesmentioning

confidence: 99%

Invariant Chain Complexes and Clusters as Platforms for MIF Signaling

Lindner

2017

Cells

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Invariant chain (Ii/CD74) has been identified as a surface receptor for migration inhibitory factor (MIF). Most cells that express Ii also synthesize major histocompatibility complex class II (MHC II) molecules, which depend on Ii as a chaperone and a targeting factor. The assembly of nonameric complexes consisting of one Ii trimer and three MHC II molecules (each of which is a heterodimer) has been regarded as a prerequisite for efficient delivery to the cell surface. Due to rapid endocytosis, however, only low levels of Ii-MHC II complexes are displayed on the cell surface of professional antigen presenting cells and very little free Ii trimers. The association of Ii and MHC II has been reported to block the interaction with MIF, thus questioning the role of surface Ii as a receptor for MIF on MHC II-expressing cells. Recent work offers a potential solution to this conundrum: Many Ii-complexes at the cell surface appear to be under-saturated with MHC II, leaving unoccupied Ii subunits as potential binding sites for MIF. Some of this work also sheds light on novel aspects of signal transduction by Ii-bound MIF in B-lymphocytes: membrane raft association of Ii-MHC II complexes enables MIF to target Ii-MHC II to antigen-clustered B-cell-receptors (BCR) and to foster BCR-driven signaling and intracellular trafficking.

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“…This is exemplified by CD74, the invariant chain of the MHCII complex [47]. In vivo, SPPL2a has a leading role in the cleavage of CD74 NTFs [64] demonstrated by its massive accumulation in B cells and dendritic cells from SPPL2a-deficient mice [57,65,66] and humans [67,68]. At the cellular level, the functional consequences of the accumulating CD74 NTF have so far only been analysed in murine SPPL2a-deficient B cells [69].…”

Section: Regulation Of Signal Transductionmentioning

confidence: 99%

Physiological functions of SPP/SPPL intramembrane proteases

Mentrup

Cabrera-Cabrera

Fluhrer

et al. 2020

Cell. Mol. Life Sci.

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Intramembrane proteolysis describes the cleavage of substrate proteins within their hydrophobic transmembrane segments. Several families of intramembrane proteases have been identified including the aspartyl proteases Signal peptide peptidase (SPP) and its homologues, the SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3. As presenilin homologues, they employ a similar catalytic mechanism as the well-studied γ-secretase. However, SPP/SPPL proteases cleave transmembrane proteins with a type II topology. The characterisation of SPP/SPPL-deficient mouse models has highlighted a still growing spectrum of biological functions and also promoted the substrate discovery of these proteases. In this review, we will summarise the current hypotheses how phenotypes of these mouse models are linked to the molecular function of the enzymes. At the cellular level, SPP/SPPL-mediated cleavage events rather provide specific regulatory switches than unspecific bulk proteolysis. By this means, a plethora of different cell biological pathways is influenced including signal transduction, membrane trafficking and protein glycosylation.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells

Cited by 20 publications

References 19 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

Invariant Chain Complexes and Clusters as Platforms for MIF Signaling

Physiological functions of SPP/SPPL intramembrane proteases

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