Scaffold Protein JLP Is Critical for CD40 Signaling in B Lymphocytes*
Scaffold Protein JLP Is Critical for CD40 Signaling in B Lymphocytes*
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DOI：
10.1074/jbc.m114.618496
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
Hui-ming Wang;Q. Yan;Tao Yang;Hui-Teng Cheng;Juan Du;K. Yoshioka;S. Kung;G. Ding
中科院分区：
文献类型：
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作者：
Hui-ming Wang;Q. Yan;Tao Yang;Hui-Teng Cheng;Juan Du;K. Yoshioka;S. Kung;G. Ding
背景：JLP在B淋巴细胞中的CD 40转运和信号传导中的作用仍然是未知的。结果：B淋巴细胞JLP缺陷导致选择性CD 40内化减少，MAPK和JNK活化。结论：JLP介导的CD 40内化是B淋巴细胞下游JNK和MAPK信号转导的重要途径。意义：我们报道了JLP在B淋巴细胞中的CD 40内化和CD 40依赖性信号转导的桥接中的新作用。B淋巴细胞表面CD 40的表达对其生物学功能和命运决定至关重要。CD 40与其同源配体CD 154的结合导致了B淋巴细胞中的一系列细胞事件，包括CD 40细胞质易位、效应分子的时间和空间组织以及CD 40诱导的信号转导级联。JLP支架蛋白在小鼠B淋巴细胞中表达。使用来自JLP缺陷小鼠的B淋巴细胞，我们观察到JLP缺陷导致在CD 154/CD 40接合后的CD 40内化缺陷。对B淋巴细胞中CD 40、JLP、动力蛋白和Rab 5之间相互作用和共定位的研究表明，CD 40内化是依赖Rab 5和动力蛋白的JLP介导的囊泡运输过程。JLP缺陷还减少了MAPK和JNK的CD 40依赖性活化，但不影响NF-κB。通过动力蛋白抑制剂（ciliobrevin D）抑制囊泡从细胞周边方向向细胞中心的运输，损害了B淋巴细胞中CD 154诱导的CD 40内化和CD 40依赖的MAPK活性。总的来说，我们的数据证明了JLP支架蛋白在脾B淋巴细胞中的CD 154触发的CD 40内化和CD 40依赖性信号传导的桥接中的新作用。
Background: The roles of JLP in CD40 trafficking and signaling in B lymphocytes remain elusive. Results: JLP deficiency in B lymphocytes resulted in selective diminished CD40 internalization and activation of MAPK and JNK. Conclusion: JLP-mediated CD40 internalization is essential for downstream JNK and MAPK signaling in B lymphocytes. Significance: We report a novel role of JLP in the bridging of CD40 internalization and CD40-dependent signaling in B lymphocytes. CD40 expression on the surface of B lymphocytes is essential for their biological function and fate decision. The engagement of CD40 with its cognate ligand, CD154, leads to a sequence of cellular events in B lymphocytes, including CD40 cytoplasmic translocation, a temporal and spatial organization of effector molecules, and a cascade of CD40-induced signal transduction. The JLP scaffold protein was expressed in murine B lymphocytes. Using B lymphocytes from jlp-deficient mice, we observed that JLP deficiency resulted in defective CD40 internalization upon CD154/CD40 engagement. Examination of interactions and co-localization among CD40, JLP, dynein, and Rab5 in B lymphocytes suggested that CD40 internalization is a process of JLP-mediated vesicle transportation that depends on Rab5 and dynein. JLP deficiency also diminished CD40-dependent activation of MAPK and JNK, but not NF-κB. Inhibiting vesicle transportation from the direction of cell periphery to the cell center by a dynein inhibitor (ciliobrevin D) impaired both CD154-induced CD40 internalization and CD40-dependent MAPK activities in B lymphocytes. Collectively, our data demonstrate a novel role of the JLP scaffold protein in the bridging of CD154-triggered CD40 internalization and CD40-dependent signaling in splenic B lymphocytes.