Processing of CD74 by the intramembrane protease SPPL2a is critical for B cell receptor dignaling in transitional B cells
08.07.2015 Hüttl S, Kläsener K, Schweizer M, Schneppenheim J, Oberg HH, Kabelitz D, Reth M, Saftig P, Schröder B. J Immunol. 2015;195(4):1548-63. The invariant chain (CD74), a chaperone in MHC class II-mediated Ag presentation, is sequentially processed by different endosomal proteases. The 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 SPPL2a deficiency mice the accumulation of NTF in endocytic vesicles leads to a B cell maturation arrest at the transitional 1 stage. We studied the impact of SPPL2a deficiency on B cell signaling. We found that the BCR-induced PI3K/Akt activation is compromised in SPPL2a(-/-) B cells. Furthermore, we found an accumulating of CD74 in SPPL2a-deficient B cells and an increased proximity of CD74 to the BCR signaling component Iga. 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 is required for proper B cell maturation. Fig. 1 Increased association between CD74 and the Iga signaling component of the BCR in SPPL2a-deficient B cells as detected by a Fab-based proximity ligation assay (Fab-PLA)