Orchestrated delivery of Legionella effectors by the Icm/Dot secretion system

uses the Icm/Dot Type IV secretion system (T4SS) to translocate a record number (300) of bacterial effectors into the host cell. Despite recent breakthrough progress in determining the structure and the localization of the secretion machinery, it is still a challenge to understand how the delivery of so many effectors is organized to avoid bottleneck effect and to allow effective manipulation of the host cell by . Here, we demonstrate that secretion of effectors is ordered and so precisely set up that it lines-up with the delivery timing required for the function of the effectors in the cell. We observe notably that the secretion order of 4 effectors targeting Rab1 is fully consistent with the sequence of their actions on Rab1. Importantly, we show that the timed delivery of an effector is not dependent on its concentration, nor on its picking-up by chaperone proteins. Conversely, this control involves c-di-GMP signaling, as a c-di-GMP synthesizing enzyme, namely the diguanylate cyclase Lpl0780/Lpp0809, significantly contributes to accurate triggering of effector secretion via a post-translational control of the T4SS machinery at the bacterial pole.