Teaching Fido new ModiFICation tricks.

Abstract

The Fic (filamentation induced by cAMP) family of proteins comprises several thousand members that are found in all domains of life [1], [2]. In bacteria, these proteins are often expressed by pathogens as virulence factors that disrupt signaling in the mammalian host cell through inhibition of one or more GTPases or kinases involved in cell signaling. By integrating surprising new insights, this Pearl highlights the spectrum of potent posttranslational modifications catalyzed by the Fic family of proteins in bacterial pathogens. We will also discuss how Fic proteins are predicted to endow bacterial pathogens with the ability to perturb essential signaling pathways in their host cells (for secreted Fic proteins) or enable the pathogen to endure stresses such as antibiotic exposure (for intracellular Fic proteins derived from toxin-antitoxin modules). All Fic family proteins (also referred to as “Fido” because the family includes Doc toxins [3]) contain a Fic domain of 100–140 amino acids that exhibits two hallmarks, striking structural similarity and a highly conserved, nine amino acid active site (Figure 1). At the structural level, Fic domains have an α-helical core consisting of six or eight α-helices (reviewed in [3], [4]). Yet, there is no significant sequence similarity among all Fic domain proteins beyond the 9-residue active site, the Fic motif. These conserved features alone did not provide clues to the function of Fic domain proteins. Only upon molecular analysis of the Vibrio parahemolyticus virulence factor VopS by the Orth group [5] was a precise enzymatic activity of Fic domain proteins revealed. This discovery set the stage for a series of unanticipated twists demonstrating that Fic domains can influence pathogenesis by inactivating target proteins involved in cell signaling by one of four posttranslational modifications: AMP, UMP, phosphocholine, or phosphate (summarized in Figure 2). Figure 1 Overview of Fic domain proteins, their targets, and their roles in bacterial virulence. Figure 2 Features and functions of effector proteins that contain a Fic domain.