Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical fot B Cell Receptor Signaling in Transitional B Cells.
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Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical fot B Cell Receptor Signaling in Transitional B Cells. / Hüttl, Susann; Kläsener, Kathrin; Schweizer, Michaela; Schneppenheim, Janna; Oberg, Hans-Heinrich; Kabelitz, Dieter; Reth, Michael; Saftig, Paul; Schröder, Bernd.
In: J IMMUNOL, Vol. 195 , No. 4, 15.08.2015, p. 1548-1563.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical fot B Cell Receptor Signaling in Transitional B Cells.
AU - Hüttl, Susann
AU - Kläsener, Kathrin
AU - Schweizer, Michaela
AU - Schneppenheim, Janna
AU - Oberg, Hans-Heinrich
AU - Kabelitz, Dieter
AU - Reth, Michael
AU - Saftig, Paul
AU - Schröder, Bernd
PY - 2015/8/15
Y1 - 2015/8/15
N2 - 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.
AB - 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.
M3 - SCORING: Journal article
VL - 195
SP - 1548
EP - 1563
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 4
ER -