Kralova Jarmila, Fabisik Matej, Pokorna Jana, Skopcova Tereza, Malissen Bernard, Brdicka Tomas
From the Laboratories of Leukocyte Signaling and.
Molecular Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic and.
J Biol Chem. 2016 Aug 5;291(32):16530-40. doi: 10.1074/jbc.M116.717157. Epub 2016 Jun 10.
Transmembrane adaptor proteins are molecules specialized in recruiting cytoplasmic proteins to the proximity of the cell membrane as part of the signal transduction process. A member of this family, SLP65/SLP76, Csk-interacting membrane protein (SCIMP), recruits a complex of SLP65/SLP76 and Grb2 adaptor proteins, known to be involved in the activation of PLCγ1/2, Ras, and other pathways. SCIMP expression is restricted to antigen-presenting cells. In a previous cell line-based study, it was shown that, in B cells, SCIMP contributes to the reverse signaling in the immunological synapse, downstream of MHCII glycoproteins. There it mainly facilitates the activation of ERK MAP kinases. However, its importance for MHCII glycoprotein-dependent ERK signaling in primary B cells has not been analyzed. Moreover, its role in macrophages and dendritic cells has remained largely unknown. Here we present the results of our analysis of SCIMP-deficient mice. In these mice, we did not observe any defects in B cell signaling and B cell-dependent responses. On the other hand, we found that, in dendritic cells and macrophages, SCIMP expression is up-regulated after exposure to GM-CSF or the Dectin-1 agonist zymosan. Moreover, we found that SCIMP is strongly phosphorylated after Dectin-1 stimulation and that it participates in signal transduction downstream of this important pattern recognition receptor. Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 because of an increased expression and sustained phosphorylation lasting at least 24 h after signal initiation.
跨膜衔接蛋白是一类专门负责在信号转导过程中将细胞质蛋白募集到细胞膜附近的分子。该家族成员之一，Csk相互作用膜蛋白（SCIMP），即SLP65/SLP76，可募集已知参与PLCγ1/2、Ras及其他信号通路激活的SLP65/SLP76和Grb2衔接蛋白复合物。SCIMP的表达仅限于抗原呈递细胞。在先前基于细胞系的研究中发现，在B细胞中，SCIMP在MHCII糖蛋白下游的免疫突触中参与反向信号传导。在那里，它主要促进ERK MAP激酶的激活。然而，其在原代B细胞中对MHCII糖蛋白依赖性ERK信号传导的重要性尚未得到分析。此外，其在巨噬细胞和树突状细胞中的作用在很大程度上仍不清楚。在此，我们展示了对SCIMP缺陷小鼠的分析结果。在这些小鼠中，我们未观察到B细胞信号传导及B细胞依赖性反应存在任何缺陷。另一方面，我们发现，在树突状细胞和巨噬细胞中，暴露于GM-CSF或Dectin-1激动剂酵母聚糖后，SCIMP的表达会上调。此外，我们发现Dectin-1刺激后SCIMP会强烈磷酸化，且它参与这一重要模式识别受体下游的信号转导。我们对SCIMP缺陷树突状细胞的分析表明，由于信号启动后至少24小时内表达增加且持续磷酸化，SCIMP特别有助于维持Dectin-1下游的长期MAP激酶信号传导和细胞因子产生。
