Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

Abstract

SUMMARY Initially discovered in the context of immunomodulation, peptidyl-prolyl cis/trans isomerases (PPIases) were soon identified as enzymes catalyzing the rate-limiting protein folding step at peptidyl bonds preceding proline residues. Intense searches revealed that PPIases are a superfamily of proteins consisting of three structurally distinguishable families with representatives in every described species of prokaryote and eukaryote and, recently, even in some giant viruses. Despite the clear-cut enzymatic activity and ubiquitous distribution of PPIases, reports on solely PPIase-dependent biological roles remain scarce. Nevertheless, they have been found to be involved in a plethora of biological processes, such as gene expression, signal transduction, protein secretion, development, and tissue regeneration, underscoring their general importance. Hence, it is not surprising that PPIases have also been identified as virulence-associated proteins. The extent of contribution to virulence is highly variable and dependent on the pleiotropic roles of a single PPIase in the respective pathogen. The main objective of this review is to discuss this variety in virulence-related bacterial and protozoan PPIases as well as the involvement of host PPIases in infectious processes. Moreover, a special focus is given to Legionella pneumophila macrophage infectivity potentiator (Mip) and Mip-like PPIases of other pathogens, as the best-characterized virulence-related representatives of this family. Finally, the potential of PPIases as alternative drug targets and first tangible results are highlighted.

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

“…Traditional antibiotic development approaches that target a limited number of bacterial components are increasingly ineffective, and therefore, novel bacterial targets must be investigated. PPIase enzymes represent one such promising novel target (2). The work presented here demonstrates that two functionally distinct PPIases are important for virulence factor production in S. aureus.…”

“…In contrast, for all other naturally occurring amino acids, steric hindrance between side chains precludes the cis form and overwhelmingly favors the trans form (2). The presence of both the cis and trans forms of proline peptide bonds has important consequences for protein tertiary structure.…”

“…Perhaps the best-studied example of a bacterial PPIase is the trigger factor Tig (a member of the FKBPs), which is found to be associated with the ribosome and assists in folding nascent peptides immediately following translation (6). Another well-studied bacterial PPIase is PrsA, a member of the parvulin family (2,5). PrsA is a membraneanchored lipoprotein located at the interface between the bacterial cell membrane and the cell wall.…”

On the role, ecology, phylogeny, and structure of dual-family immunophilins

“…I presume that the majority of DFIs are functional PPIases and may also have the expected chaperone activity. As a corollary, they may be explored as therapeutic targets (Schiene-Fischer 2015;Ünal and Steinert 2014), perhaps through the designing of selective bispecific drugs (Dunyak et al 2015;Yang et al 2015a).…”

Legionella-protozoa-nematode interactions in aquatic biofilms and influence of Mip on Caenorhabditis elegans colonization

“…Biochemical analyzes revealed that the collagen-derived peptide P290 binds to a specific hydrophobic cavity of Mip, and based on NMR data and docking studies a model for the mode of interaction of P290 and Mip was developed. Moreover, guinea pig infections revealed that Mip contributes to alveolar septum transmigration of L. pneumophila and subsequently to the bacterial spread to the spleen (Cianciotto et al, 1995;Uenal et al, 2011;Ünala and Steinert, 2014;Wagner et al, 2007).…”