The type III effector EspF coordinates membrane trafficking by the spatiotemporal activation of two eukaryotic signaling pathways

被引:102
作者
Alto, Neal M.
Weflen, Andrew W.
Rardin, Matthew J.
Yarar, Defne
Lazar, Cheri S.
Tonikian, Raffi
Koller, Antonius
Taylor, Susan S.
Boone, Charles
Sidhu, Sachdev S.
Schmid, Sandra L.
Hecht, Gail A.
Dixon, Jack E. [1 ]
机构
[1] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA
[5] Univ Illinois, Sect Digest Dis & Nutr, Dept Med, Chicago, IL 60612 USA
[6] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA
[7] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5S 3E1, Canada
[8] Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON M5S 3E1, Canada
[9] Genencor Inc, Dept Prot Engn, San Francisco, CA 94080 USA
关键词
D O I
10.1083/jcb.200705021
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Bacterial toxins and effector proteins hijack eukaryotic enzymes that are spatially localized and display rapid signaling kinetics. However, the molecular mechanisms by which virulence factors engage highly dynamic substrates in the host cell environment are poorly understood. Here, we demonstrate that the enteropathogenic Escherichia coli (EPEC) type III effector protein EspF nucleates a multiprotein signaling complex composed of eukaryotic sorting nexin 9 (SNX9) and neuronal Wiskott-Aldrich syndrome protein (N-WASP). We demonstrate that a specific and high affinity association between EspF and SNX9 induces membrane remodeling in host cells. These membrane-remodeling events are directly coupled to N-WASP/Arp2/3-mediated actin nucleation. In addition to providing a biochemical mechanism of EspF function, we find that EspF dynamically localizes to membrane-trafficking organelles in a spatiotemporal pattern that correlates with SNX9 and N-WASP activity in living cells. Thus, our findings suggest that the EspF-dependent assembly of SNX9 and N-WASP represents a novel form of signaling mimicry used to promote EPEC pathogenesis and gastrointestinal disease.
引用
收藏
页码:1265 / 1278
页数:14
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