Evolution and function of bacterialRCC1repeat effectors

Abstract

Intracellular bacterial pathogens harbour genes, the closest homologues of which are found in eukaryotes. Regulator of chromosome condensation 1 (RCC1) repeat proteins are phylogenetically widespread and implicated in protein–protein interactions, such as the activation of the small GTPase Ran by its cognate guanine nucleotide exchange factor, RCC1. Legionella pneumophila and Coxiella burnetii, the causative agents of Legionnaires' disease and Q fever, respectively, harbour RCC1 repeat coding genes. Legionella pneumophila secretes the RCC1 repeat ‘effector’ proteins LegG1, PpgA and PieG into eukaryotic host cells, where they promote the activation of the pleiotropic small GTPase Ran, microtubule stabilisation, pathogen vacuole motility and intracellular bacterial growth as well as host cell migration. The RCC1 repeat effectors localise to the pathogen vacuole or the host plasma membrane and target distinct components of the Ran GTPase cycle, including Ran modulators and the small GTPase itself. Coxiella burnetii translocates the RCC1 repeat effector NopA into host cells, where the protein localises to nucleoli. NopA binds to Ran GTPase and promotes the nuclear accumulation of Ran(GTP), thus pertubing the import of the transcription factor NF‐κB and innate immune signalling. Hence, divergent evolution of bacterial RCC1 repeat effectors defines the range of Ran GTPase cycle targets and likely allows fine‐tuning of Ran GTPase activation by the pathogens at different cellular sites.

Migration of Acanthamoeba through Legionella biofilms is regulated by the bacterial Lqs‐LvbR network, effector proteins and the flagellum

“…The activation of Ran GTPase by the L . pneumophila RCC1 repeat effectors promotes microtubule stabilization, LCV motility and cell migration (Rothmeier et al ., 2013; Simon et al ., 2014; Swart et al ., 2020a). Given the cell migration phenotypes of the ∆ legG1 , ∆ ppgA and ∆ legG1 ‐∆ ppgA mutant strains, presumably the effectors also positively regulate the microtubule cytoskeleton and cell migration of A .…”

“…LegG1 and PpgA are RCC1 repeat effectors, which localize to LCVs or the plasma membrane, target the activation cycle of the small GTPase Ran and activate Ran either at the LCV or the plasma membrane respectively (Rothmeier et al, 2013;Swart et al, 2020b). The activation of Ran GTPase by the L. pneumophila RCC1 repeat effectors promotes microtubule stabilization, LCV motility and cell migration (Rothmeier et al, 2013;Simon et al, 2014;Swart et al, 2020a). Given the cell migration phenotypes of the ΔlegG1, ΔppgA and ΔlegG1-ΔppgA mutant strains, presumably the effectors also positively regulate the microtubule cytoskeleton and cell migration of A. castellanii moving through biofilms.…”

TheLegionella-driven PtdIns(4)Pgradient at LCV-ER membrane contact sites promotes Vap-, OSBP- and Sac1-dependent pathogen vacuole remodeling

“…330 different “effector” proteins into host cells [6, 7]. These effector proteins subvert pivotal host cell processes, including the endocytic, secretory, retrograde and autophagy pathways, lipid metabolism, transcription, translation, and apoptosis [8–12].…”

Chromosome-scale assemblies of Acanthamoeba castellanii genomes provide insights into Legionella pneumophila infection-related chromatin re-organization

“…To establish the LCV and replicate, L. pneumophila secretes over 300 effector proteins into the host cytoplasm via a type four secretion system (T4SS) called Dot/Icm [15], thereby manipulating host pathways and redirecting nutrients to the LCV [16,17]. In the early stages of infection, many of these proteins target the host secretory pathway, including several small GTPases, to recruit endoplasmic reticulum-derived vesicles to the LCV [18]. During the intracellular cycle, a wider range of processes, including membrane trafficking, cytoskeleton dynamics, and signal transduction pathways, are targeted by these effectors [19,20].…”