| First Author | Schneppenheim J | Year | 2013 |
| Journal | J Exp Med | Volume | 210 |
| Issue | 1 | Pages | 41-58 |
| PubMed ID | 23267015 | Mgi Jnum | J:194664 |
| Mgi Id | MGI:5474495 | Doi | 10.1084/jem.20121069 |
| Citation | Schneppenheim J, et al. (2013) The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain. J Exp Med 210(1):41-58 |
| abstractText | Regulated intramembrane proteolysis is a central cellular process involved in signal transduction and membrane protein turnover. The presenilin homologue signal-peptide-peptidase-like 2a (SPPL2a) has been implicated in the cleavage of type 2 transmembrane proteins. We show that the invariant chain (li, CD74) of the major histocompatability class II complex (MHCII) undergoes intramembrane proteolysis mediated by SPPL2a. B lymphocytes of SPPL2a(-/-) mice accumulate an N-terminal fragment (NTF) of CD74, which severely impairs membrane traffic within the endocytic system and leads to an altered response to B cell receptor stimulation, reduced BAFF-R surface expression, and accumulation of MHCII in transitional developmental stage T1 B cells. This results in significant loss of B cell subsets beyond the T1 stage and disrupted humoral immune responses, which can be recovered by additional ablation of CD74. Hence, we provide evidence that regulation of CD74-NTF levels by SPPL2a is indispensable for B cell development and function by maintaining trafficking and integrity of MHCII-containing endosomes, highlighting SPPL2a as a promising pharmacological target for depleting and/or modulating B cells. |
