The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain.
The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain.
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DOI：
10.1084/jem.20121069
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发表时间：
2013-01-14
期刊：
影响因子：
--
通讯作者：
Schröder B
中科院分区：
文献类型：
--
作者：
Schneppenheim J;Dressel R;Hüttl S;Lüllmann-Rauch R;Engelke M;Dittmann K;Wienands J;Eskelinen EL;Hermans-Borgmeyer I;Fluhrer R;Saftig P;Schröder B
膜内蛋白水解酶SPPL2a裂解不变链(CD74)的NTF，CD74对于含有MHC-II类的内小体的正常运输是必不可少的，从而对B细胞的发育和功能是必不可少的。膜内蛋白水解酶是参与信号转导和膜蛋白周转的中心细胞过程。早老素同源信号肽-肽酶样蛋白2a(SPPL2a)参与了2型跨膜蛋白的切割。我们发现主要组织相容性II类复合体(MHCII)的不变链(Li，CD74)经历了SPPL2a介导的膜内蛋白分解。SPPL2a−/−小鼠的B淋巴细胞积聚CD74N末端片段，严重损害细胞内膜的运输，导致对B细胞受体刺激的反应改变，BAFF-R表面表达减少，并在发育过渡期的T1 B细胞中积聚MHCII。这会导致超过T1阶段的B细胞亚群的显著丧失，并扰乱体液免疫反应，这可以通过额外的CD74消融来恢复。因此，我们提供的证据表明，SPPL2a通过维持含有MHCII的内体的运输和完整性，调节CD74-NTF水平对于B细胞的发育和功能是不可或缺的，并强调SPPL2a是耗尽和/或调节B细胞的一个有前景的药理靶点。
The intramembrane protease SPPL2a cleaves the NTF of invariant chain (CD74), which is essential for normal trafficking of MHC class II–containing endosomes and thus for B cell development and function. 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.
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缺乏不变链表达的小鼠中有缺陷的主要组织相容性复合物II类组装，运输，肽的采集和CD4+ T细胞的选择。
DOI：
10.1084/jem.177.6.1699
发表时间：
1993-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bikoff EK;Huang LY;Episkopou V;van Meerwijk J;Germain RN;Robertson EJ
通讯作者：
Robertson EJ
影响因子：
21.3
作者：
Fluhrer, Regina;Grammer, Gudula;Haass, Christian
通讯作者：
Haass, Christian
影响因子：
4.8
作者：
Barois, N;Forquet, F;Davoust, J
通讯作者：
Davoust, J
DOI：
10.1073/pnas.0708874105
发表时间：
2008-03-04
影响因子：
11.1
作者：
De Gassart, Aude;Camosseto, Voahirana;Gatti, Evelina
通讯作者：
Gatti, Evelina
影响因子：
4.8
作者：
Friedmann, E;Lemberg, MK;Martoglio, B
通讯作者：
Martoglio, B