Abstract
Bacterial contact-dependent growth inhibition (CDI) is mediated by the CdiA/CdiB family of two-partner secretion proteins. Each CdiA protein exhibits a distinct growth inhibition activity, which resides in the polymorphic C-terminal region (CdiA-CT). CDI+ cells also express unique CdiI immunity proteins that specifically block the activity of cognate CdiA-CT, thereby protecting the cell from autoinhibition. Here we show that many CDI systems contain multiple cdiA gene fragments that encode CdiA-CT sequences. These “orphan” cdiA-CT genes are almost always associated with downstream cdiI genes to form cdiA-CT/cdiI modules. Comparative genome analyses suggest that cdiA-CT/cdiI modules are mobile and exchanged between the CDI systems of different bacteria. In many instances, orphan cdiA-CT/cdiI modules are fused to full-length cdiA genes in other bacterial species. Examination of cdiA-CT/cdiI modules from Escherichia coli EC93, E. coli EC869, and Dickeya dadantii 3937 confirmed that these genes encode functional toxin/immunity pairs. Moreover, the orphan module from EC93 was functional in cell-mediated CDI when fused to the N-terminal portion of the EC93 CdiA protein. Bioinformatic analyses revealed that the genetic organization of CDI systems shares features with rhs (rearrangement hotspot) loci. Rhs proteins also contain polymorphic C-terminal regions (Rhs-CTs), some of which share significant sequence identity with CdiA-CTs. All rhs genes are followed by small ORFs representing possible rhsI immunity genes, and several Rhs systems encode orphan rhs-CT/rhsI modules. Analysis of rhs-CT/rhsI modules from D. dadantii 3937 demonstrated that Rhs-CTs have growth inhibitory activity, which is specifically blocked by cognate RhsI immunity proteins. Together, these results suggest that Rhs plays a role in intercellular competition and that orphan gene modules expand the diversity of toxic activities deployed by both CDI and Rhs systems.
Highlights
Many bacteria lead social lives in communities where they cooperate and compete with members of their own species, as well as those of other species [1]
Recent work from our laboratories has shown that many bacteria express contact-dependent growth inhibition (CDI) systems in which stick-like proteins on the cell surface deliver toxic tips into target cells
Over 60 distinct toxic tips have been identified in bacteria, and our data indicate that each CDI+ cell expresses a specific immunity protein that binds to its cognate toxin and inactivates it to prevent cell suicide
Summary
Many bacteria lead social lives in communities where they cooperate and compete with members of their own species, as well as those of other species [1]. One mechanism of bacterial communication is quorum sensing, in which small signaling molecules are released to coordinate group behavior when a critical cell density has been attained [2]. Other modes of communication based on direct cell-to-cell contact have recently been identified in bacteria. Contact-dependent signaling helps to coordinate cell aggregation and fruiting body formation in Myxococcus xanthus [3], and is exploited to inhibit the growth of neighboring cells. Contact-dependent growth inhibition (CDI) was first described in the Escherichia coli isolate EC93 [4], and has subsequently been demonstrated in Dickeya dadantii 3937 [5]. CDI is mediated by the CdiB-CdiA two-partner secretion system. CdiB is a predicted outer membrane b-barrel protein that is required for secretion and presentation of the CdiA exoprotein on the cell surface [6,7]. CdiI protects EC93 cells from CdiA-mediated growth autoinhibition [5]
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