Covalent attachment and Pro‐Pro endopeptidase (PPEP‐1)‐mediated release of Clostridium difficile cell surface proteins involved in adhesion

Summary In the past decade, Clostridium difficile has emerged as an important gut pathogen. This anaerobic, Gram‐positive bacterium is the main cause of infectious nosocomial diarrhea. Whereas much is known about the mechanism through which the C. difficile toxins cause diarrhea, relatively little is known about the dynamics of adhesion and motility, which is mediated by cell surface proteins. This review will discuss the recent advances in our understanding of the sortase‐mediated covalent attachment of cell surface (adhesion) proteins to the peptidoglycan layer of C. difficile and their release through the action of a highly specific secreted metalloprotease (Pro‐Pro endopeptidase 1, PPEP‐1). Specific emphasis will be on a model in which PPEP‐1 and its substrates control the switch from a sessile to motile phenotype in C. difficile, and how this is regulated by the cyclic dinucleotide c‐di‐GMP (3′‐5′ cyclic dimeric guanosine monophosphate). Two C. difficile LPxTG‐like proteins (CD2831 and CD3246), involved in adhesion, are covalently attached to the peptidoglycan layer via a sortase‐mediated reaction. Release of these proteins is mediated by the activity of a highly specific secreted C. difficile protease, Pro‐Pro endopeptidase 1 (PPEP‐1), suggesting a role for this protease in the switch from a sessile to motile lifestyle in C. difficile