Rac and Rho compete to cooperate

Short, Ben

doi:10.1083/jcb.2154if

Cited by 1 publication

(1 citation statement)

References 6 publications

(6 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Altogether these results suggest that the role of IpgB1 during cell-to-cell spread is to activate Rac1 to antagonize the recruitment of RhoA (Fig 9, Wild Type). The spatial and temporal antagonism between Rac1 and RhoA has been well documented in the cell biology field [27][28][29][30][31][32]. During cell migration, Rac1 and RhoA are found predominantly at the leading and trailing edges of the cell, respectively [31].…”

Section: How Does Ipgb1 Antagonize the Recruitment Of Rhoa?mentioning

confidence: 99%

The type three secretion system effector protein IpgB1 promotes Shigella flexneri cell-to-cell spread through double-membrane vacuole escape

et al. 2022

View full text Add to dashboard Cite

S. flexneri is an important human pathogen that causes bacillary dysentery. During infection, S. flexneri invades colonic epithelial cells, hijacks the host cell cytoskeleton to move in the cytosol of infected cells, and spreads from cell to cell through formation of membrane protrusions that project into adjacent cells and resolve into double membrane vacuoles (DMVs). S. flexneri cell-to-cell spread requires the integrity of the bacterial type three secretion system (T3SS). However, the exact role of the T3SS effector proteins in the dissemination process remains poorly understood. Here, we investigated the role of the T3SS effector protein IpgB1 in S. flexneri dissemination. IpgB1 was previously characterized as a guanine nucleotide exchange factor (GEF) that contributes to invasion. In addition to the invasion defect, we showed that the ipgB1 mutant formed smaller infection foci in HT-29 cells. Complementation of this phenotype required the GEF activity of IpgB1. Using live confocal microscopy, we showed that the ipgB1 mutant is specifically impaired in DMV escape. Depletion of Rac1, the host cell target of IpgB1 during invasion, as well as pharmacological inhibition of Rac1 signaling, reduced cell-to-cell spread and DMV escape. In a targeted siRNA screen, we uncovered that RhoA depletion restored ipgB1 cell-to-cell spread and DMV escape, revealing a critical role for the IpgB1-Rac1 axis in antagonizing RhoA-mediated restriction of DMV escape. Using an infant rabbit model of shigellosis, we showed that the ipgB1 mutant formed fewer and smaller infection foci in colons of infected animals, which correlated with attenuated symptoms of disease, including epithelial fenestration and bloody diarrhea. Our results demonstrate that, in addition to its role during invasion, IpgB1 modulates Rho family small GTPase signaling to promote cell-to-cell spread, DMV escape, and S. flexneri pathogenesis.

show abstract