Bacterial virulence: Shigella shoots, Shigella scores

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The effector invasion plasmid antigen B, which targets the activity of the anaphase-promoting complex, retards cell-cycle progression and promotes bacterial colonization of the intestinal epithelium by Shigella flexneri.

A new study published in Cell reports that Shigella flexneri influences intestinal epithelial-cell renewal during infection by delivering the type III secretion system (T3SS) effector invasion plasmid antigen B (IpaB) into host cells. The authors show that IpaB targets the activity of the anaphase-promoting complex (APC), retarding cell-cycle progression and thereby promoting bacterial colonization of the intestinal epithelium.

S. flexneri can efficiently colonize the human intestinal epithelium despite the ability of the intestinal epithelium to renew itself every few days. During colonization, S. flexneri delivers a number of effector proteins into the host cell using the T3SS, which is a special protein-export apparatus. This study investigated the role of one of these effector proteins — IpaB.

Iwai and colleagues performed yeast two-hybrid screening of a HeLa-cell cDNA library and found that IpaB interacts with an APC inhibitor called Mad2L2. The APC is an E3 ubiquitin ligase that targets substrates for degradation and initiates anaphase. The APC is activated by the binding of co-activator proteins that associate with the APC during specific periods of the cell cycle. One of these proteins is Cdc20 homologue 1 (Cdh1), which binds to the APC (APC^Cdh1) during the late mitotic and G1 phases of the eukaryotic cell cycle; it has recently been suggested that Mad2L2 suppresses APC activation by Cdh1.

S. flexneri infection of HeLa cells, as well as of rabbit intestinal-crypt progenitors, led to the unscheduled activation of APC^Cdh1 in the G2/M phase, owing to the interaction of IpaB with Mad2L2. So, the IpaB that is delivered by S. flexneri interferes with the binding of Mad2L2 to APC^Cdh1, leading to the unscheduled activation of the APC. This leads to the premature degradation of cyclin B1, a regulatory subunit that acts together with a kinase to determine a cell's progress through the cell cycle. IpaB can, therefore, slow cell-cycle progression in eukaryotic target cells.

How does this activity contribute to S. flexneri colonization of the intestinal epithelium? The authors prepared a mixture of bacteria that comprised equal numbers of S. flexneri expressing IpaB and an IpaB mutant that is translocated by the T3SS but interacts comparatively weakly with Mad2L2. After inoculating rabbit ileal loops with the mixture, the colonization rate of the bacteria that expressed wild-type IpaB was observed to be considerably more efficient than that of S. flexneri expressing the mutant IpaB, showing that the IpaB–Mad2L2 interaction is functionally important for bacterial colonization.

This is the first evidence that shows that a bacterial type III-secreted effector can target the activity of the APC in intestinal epithelial cells and directly modulate the progression of the eukaryotic cell cycle.

Sharon Ahmad

References

Iwai, H. et al. A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell 130, 611–623 (2007). | Article | PubMed |