Abstract
Type 3 secretion systems (T3SSs) are conserved bacterial nanomachines that inject virulence proteins (effectors) into eukaryotic cells during infection. Due to their ability to inject heterologous proteins into human cells, these systems are being developed as therapeutic delivery devices. The T3SS assembles a translocon pore in the plasma membrane and then docks onto the pore. Docking activates effector secretion through the pore and into the host cytosol. Here, using Shigella flexneri, a model pathogen for the study of type 3 secretion, we determined the molecular mechanisms by which host intermediate filaments trigger docking and enable effector secretion. We show that the interaction of intermediate filaments with the translocon pore protein IpaC changed the pore's conformation in a manner that was required for docking. Intermediate filaments repositioned residues of the Shigella pore protein IpaC that are located on the surface of the pore and in the pore channel. Restricting these conformational changes blocked docking in an intermediate filament-dependent manner. These data demonstrate that a host-induced conformational change to the pore enables T3SS docking and effector secretion, providing new mechanistic insight into the regulation of type 3 secretion.
Highlights
Type 3 secretion systems (T3SSs) are present in and are essential for the virulence of more than 30 bacterial pathogens of humans, animals, and plants
The T3SS apparatus consists of a base that spans both bacterial membranes, a needle that is anchored in the base and extends from the bacterial surface, and a tip complex that is positioned at the distal end of the needle and prevents non-specific secretion [1,2,3]
Since the interaction of intermediate filaments with the Shigella translocon pore protein IpaC is dispensable for pore formation but required for docking [7], we hypothesized that the interaction of IpaC with intermediate filaments alters the conformation of the translocon pore in a manner that enables docking
Summary
Type 3 secretion systems (T3SSs) are present in and are essential for the virulence of more than 30 bacterial pathogens of humans, animals, and plants. T3SSs deliver bacterial effector proteins into the cytosol of eukaryotic host cells. Effector proteins manipulate cellular signaling in ways that promote bacterial virulence. Whereas effector proteins are specific to each pathogen, the T3SS apparatus is highly conserved across bacterial species [4]. The molecular context that triggers secretion and translocation of effector proteins through the T3SS apparatus into the host cell is complex. The Shigella translocon pore protein IpaC and its homologs interact with intermediate filaments [7,8,9], eukaryotic cytoskeletal proteins. Neither the signal that activates secretion nor the mechanism by which docking is enabled by the interaction of intermediate filaments with the pore has been determined
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