Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella
Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella
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DOI：
10.1038/emboj.2010.28
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发表时间：
2010-04-21
期刊：
影响因子：
11.4
通讯作者：
Teasdale, Rohan D.
中科院分区：
文献类型：
--
作者：
Kerr, Markus C.;Wang, Jack T. H.;Teasdale, Rohan D.
3-磷酸化的磷酸肌醇（3-PtdIn）协调胞内病原体如沙门氏菌利用的内吞运输途径以进入细胞。为了感染宿主，沙门氏菌破坏其正常的巨胞饮细胞活性，操纵该过程以产生细胞内复制小生境。通过干扰突变体、siRNA介导的敲低或药理学手段破坏PtdIns（5）激酶PIKfyve，可抑制肠沙门氏菌鼠伤寒血清型在上皮细胞中的细胞内复制。通过延时3D（4D）视频显微镜监测巨胞饮的动力学，揭示了PI（3，5）P-2在巨胞饮体-晚期内体/溶酶体融合中的新的和重要的作用，这与小GT受体Rab 7的作用不同。该PI（3，5）P-2依赖性步骤是通过形成沙门氏菌诱导的细丝（SIF）和参与沙门氏菌致病岛2编码的3型分泌系统（SPI 2-T3 SS）而使含沙门氏菌的空泡（SCV）适当成熟所必需的。最后，尽管巨噬细胞中PIKfyve的抑制确实抑制了沙门氏菌的复制，但它似乎也破坏了巨噬细胞的杀菌反应。The EMBO Journal（2010）29，1331-1347. doi：10.1038/doj.2010.28; 2010年3月18日在线发布
3-phosphorylated phosphoinositides (3-PtdIns) orchestrate endocytic trafficking pathways exploited by intracellular pathogens such as Salmonella to gain entry into the cell. To infect the host, Salmonellae subvert its normal macropinocytic activity, manipulating the process to generate an intracellular replicative niche. Disruption of the PtdIns(5) kinase, PIKfyve, be it by interfering mutant, siRNA-mediated knockdown or pharmacological means, inhibits the intracellular replication of Salmonella enterica serovar typhimurium in epithelial cells. Monitoring the dynamics of macropinocytosis by time-lapse 3D (4D) videomicroscopy revealed a new and essential role for PI(3,5)P-2 in macropinosome-late endosome/lysosome fusion, which is distinct from that of the small GTPase Rab7. This PI(3,5)P-2-dependent step is required for the proper maturation of the Salmonella-containing vacuole (SCV) through the formation of Salmonella-induced filaments (SIFs) and for the engagement of the Salmonella pathogenicity island 2-encoded type 3 secretion system (SPI2-T3SS). Finally, although inhibition of PIKfyve in macrophages did inhibit Salmonella replication, it also appears to disrupt the macrophage's bactericidal response. The EMBO Journal (2010) 29, 1331-1347. doi: 10.1038/emboj.2010.28; Published online 18 March 2010