B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8− dendritic cells require the intramembrane endopeptidase SPPL2A

Bergmann, H; Yabas, Mehmet; Short, Alanna; Miosge, Lisa A.; Barthel, Nadine; Teh, Charis E.; Roots, Carla; Bull, Katherine; Jeelall, Yogesh; Horikawa, Keisuke; Whittle, Belinda; Balakishnan, Bhavani; Sjollema, Geoff; Bertram, Edward M.; Mackay, Fabienne; Rimmer, Andrew; Cornall, Richard J.; Field, Matthew A.; Andrews, T. Daniel; Goodnow, Christopher C.; Enders, Anselm

doi:10.1084/jem.20121076

Cited by 76 publications

(103 citation statements)

References 40 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: 72%

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%

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 Zfp318 point mutant strain was identified by flow cytometry screening of peripheral blood lymphocytes in third-generation offspring from ENU-treated C57BL/6 mice as described (39). Identification of the causal mutation was done by whole exome sequencing as described (40,41). The Zfp318 −/− mice were generated by H.H.…”

Section: Methodsmentioning

confidence: 99%

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Enders¹,

Short²,

Miosge³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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IgD and IgM are produced by alternative splicing of long primary RNA transcripts from the Ig heavy chain (Igh) locus and serve as the receptors for antigen on naïve mature B lymphocytes. IgM is made selectively in immature B cells, whereas IgD is coexpressed with IgM when the cells mature into follicular or marginal zone B cells, but the transacting factors responsible for this regulated change in splicing have remained elusive. Here, we use a genetic screen in mice to identify ZFP318, a nuclear protein with two U1-type zinc fingers found in RNA-binding proteins and no known role in the immune system, as a critical factor for IgD expression. A point mutation in an evolutionarily conserved lysine-rich domain encoded by the alternatively spliced Zfp318 exon 10 abolished IgD expression on marginal zone B cells, decreased IgD on follicular B cells, and increased IgM, but only slightly decreased the percentage of B cells and did not decrease expression of other maturation markers CD21, CD23, or CD62L. A targeted Zfp318 null allele extinguished IgD expression on mature B cells and increased IgM. Zfp318 mRNA is developmentally regulated in parallel with IgD, with little in pro-B cells, moderate amounts in immature B cells, and high levels selectively in mature follicular B cells. These findings identify ZFP318 as a crucial factor regulating the expression of the two major antibody isotypes on the surface of most mature B cells.IgHm | IgHd | immunoglobulin isotype |

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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

142

102

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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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B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8− dendritic cells require the intramembrane endopeptidase SPPL2A

Abstract: Mice lacking activity of the intramembrane protease SPPL2A exhibit humoral immunodeficiency and lack mature B cell subsets.

Cited by 76 publications

References 40 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

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

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

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