Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins

Abstract

Summary ADP-ribosylation of proteins can profoundly impact their function and serves as an effective mechanism by which bacterial toxins impair eukaryotic cell processes. Here we report the discovery that bacteria also employ ADP-ribosylating toxins against each other during interspecies competition. We demonstrate that one such toxin from Serratia proteamaculans interrupts the division of competing cells by modifying the essential bacterial tubulin-like protein, FtsZ, adjacent to its protomer interface, blocking its capacity to polymerize. The structure of the toxin in complex with its immunity determinant revealed two distinct modes of inhibition: active site occlusion and enzymatic removal of ADP-ribose modifications. We show that each is sufficient to support toxin immunity; however, the latter additionally provides unprecedented broad protection against non-cognate ADP-ribosylating effectors. Our findings reveal how an interbacterial arms race has produced a unique solution for safeguarding the integrity of bacterial cell division machinery against inactivating post-translational modifications.

Host Adaptation PredisposesPseudomonas aeruginosato Type VI Secretion System-Mediated Predation by theBurkholderia cepaciaComplex

“…T6SSs use a bacteriophage-like mechanism to deliver effector proteins directly into target bacterial or eukaryotic cells (Basler et al, 2012;Hachani et al, 2016;Hood et al, 2010;Pukatzki et al, 2007). Antibacterial T6SS effectors disrupt diverse biological processes within target cells, and cognate immunity proteins protect T6SS-producing cells from autotoxicity (Ahmad et al, 2019;Russell et al, 2014;Ting et al, 2018). Type VI secretion (T6S) has been studied in the Bcc pathogen Burkholderia cenocepacia strain J2315 (BcJ2315), which produces a T6SS that is important for infection of macrophages and influences the immune response to this pathogen (Aubert et al, 2015;Hunt et al, 2004;Rosales-Reyes et al, 2012).…”

Targeting ADP-ribosylation as an antimicrobial strategy

“…Following the modification, FtsZ loses its ability to polymerise resulting in the alteration of cytoskeletal structure and leading to cell death. The ARH-like hydrolase Tri1 can revert the modification [268].…”

Causalities of war: The connection between type VI secretion system and microbiota

“…"Cargo" effectors noncovalently interact with structural components (VgrG/PAAR/Hcp), whereas "specialised" or "evolved" effectors contain additional effector domains within one protein (VgrG/PAAR/Hcp). Other targeted processes are bacterial cell division (e.g., blocking FtsZ polymerisation; Ting et al, 2018;Wood et al, 2019), protein synthesis , or availability of dinucleotides such as NADP+ and ATP to cripple prey cells (Ahmad et al, 2019;Whitney et al, 2015). (III) Model of contraction-based firing.…”

“…(V) Model of human with outline of the intestine focusing on region of interest Miyata, Unterweger, Rudko, & Pukatzki, 2013). Other targeted processes are bacterial cell division (e.g., blocking FtsZ polymerisation; Ting et al, 2018;Wood et al, 2019), protein synthesis , or availability of dinucleotides such as NADP+ and ATP to cripple prey cells (Ahmad et al, 2019;Whitney et al, 2015). Some T6SS effectors function as metal ion scavenging proteins, which may result in starvation instead of cell damage and impact the community more broadly (Figure 2; Lin et al, 2017).…”