Rab5 is critical for SNAP23 regulated granule-granule fusion during compound exocytosis.
Rab5 is critical for SNAP23 regulated granule-granule fusion during compound exocytosis.
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DOI：
10.1038/s41598-017-15047-8
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发表时间：
2017-11-10
影响因子：
4.6
通讯作者：
Sagi-Eisenberg R
中科院分区：
文献类型：
--
作者：
Klein O;Roded A;Zur N;Azouz NP;Pasternak O;Hirschberg K;Hammel I;Roche PA;Yatsu A;Fukuda M;Galli SJ;Sagi-Eisenberg R
复合胞吐被认为是胞吐的最大模式，在此期间，分泌颗粒（SG）的膜彼此融合以形成通道，通过该通道释放颗粒的全部内容物。复合胞吐作用的潜在机制在很大程度上仍未得到解决。在这里，我们表明，小GTTRab 5，一个已知的调节内吞作用，是关键的复合胞吐肥大细胞。Rab 5的沉默将受体触发的分泌从化合物转变为完全胞吐模式，其中SG单独与质膜融合。此外，我们发现Rab 5对于Fcε RI触发的SNARE蛋白SNAP 23与SGs的缔合是必需的。提供了SNAP 23参与活化细胞中发生的同型SG融合的直接证据。最后，我们发现，这种融合事件是通过抑制IKKβ2激酶来阻止的，然而，SNAP 23的磷酸化缺陷突变体和磷酸化模拟突变体都不能介导触发细胞中的同型SG融合。综上所述，我们的研究结果确定Rab 5作为一个迄今未被认识的调节剂的复合胞吐作用，这是必不可少的SNAP 23介导的颗粒-颗粒融合。我们的研究结果还涉及在同型SG融合中控制SNAP 23 SNARE功能的磷酸化循环。
Compound exocytosis is considered the most massive mode of exocytosis, during which the membranes of secretory granules (SGs) fuse with each other to form a channel through which the entire contents of their granules is released. The underlying mechanisms of compound exocytosis remain largely unresolved. Here we show that the small GTPase Rab5, a known regulator of endocytosis, is pivotal for compound exocytosis in mast cells. Silencing of Rab5 shifts receptor-triggered secretion from a compound to a full exocytosis mode, in which SGs individually fuse with the plasma membrane. Moreover, we show that Rab5 is essential for FcεRI-triggered association of the SNARE protein SNAP23 with the SGs. Direct evidence is provided for SNAP23 involvement in homotypic SG fusion that occurs in the activated cells. Finally, we show that this fusion event is prevented by inhibition of the IKKβ2 kinase, however, neither a phosphorylation-deficient nor a phosphomimetic mutant of SNAP23 can mediate homotypic SG fusion in triggered cells. Taken together our findings identify Rab5 as a heretofore-unrecognized regulator of compound exocytosis that is essential for SNAP23-mediated granule-granule fusion. Our results also implicate phosphorylation cycles in controlling SNAP23 SNARE function in homotypic SG fusion.
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影响因子：
2.4
作者：
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通讯作者：
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作者：
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