The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain

Beisner, Daniel R.; Langerak, Petra; Parker, Albert E.; Dahlberg, Carol; Otero, Francella J.; Sutton, Sue; Poirot, Laurent; Barnes, Whitney; Young, Michael A.; Niessen, Sherry; Wiltshire, Tim; Bodendorf, Ursula; Martoglio, Bruno; Cravatt, Benjamin F.; Cooke, M.

doi:10.1084/jem.20121072

Cited by 81 publications

(111 citation statements)

References 29 publications

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“…Furthermore, functionality of the remaining B cells is considerably impaired with regard to Ig production. 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).…”

supporting

confidence: 71%

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: 71%

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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“…Accumulation of the membrane-bound invariant chain fragment prevents proper B-cell development. Hence, SPPL2a inhibition might be a strategy to treat B cell-dependent autoimmune diseases [59,60].…”

Section: Aspartate Impsmentioning

confidence: 99%

Intramembrane proteases as drug targets

Verhelst

2017

The FEBS Journal

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Proteases are considered attractive drug targets. Various drugs targeting classical, soluble proteases have been approved for treatment of human disease. Intramembrane proteases (IMPs) are a more recently discovered group of proteolytic enzymes. They are embedded in lipid bilayers and their active sites are located in the plane of a membrane. All four mechanistic families of IMPs have been linked to disease, but currently, no drugs against IMPs have entered the market. In this review, I will outline the function of IMPs with a focus on the ones involved in human disease, which includes Alzheimer's disease, cancer, and infectious diseases by microorganisms. Inhibitors of IMPs are known for all mechanistic classes, but are not yet very potent or selective – aside from those targeting γ‐secretase. I will here describe the different features of IMP inhibitors and discuss a list of issues that need attention in the near future in order to improve the drug development for IMPs.

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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

139

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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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The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain

Abstract: The protease Sppl2a cleaves the N-terminal fragment of invariant chain (CD74) and is required for efficient B cell development and function.

Cited by 81 publications

References 29 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

Intramembrane proteases as drug targets

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

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