title: Regulated intramembrane proteolysis of the virulence activator TcpP in Vibrio cholerae is initiated by the tail-specific protease (Tsp).
abstract: Vibrio cholerae uses a multiprotein transcriptional regulatory cascade to control expression of virulence factors cholera toxin and toxin-co-regulated pilus. Two proteins in this cascade are ToxR and TcpP - unusual membrane-localized transcription factors with relatively undefined periplasmic domains and transcription activator cytoplasmic domains. TcpP and ToxR function with each other and two other membrane-localized proteins, TcpH and ToxS, to activate transcription of toxT, encoding the direct activator of toxin and pilus genes. Under some conditions, TcpP is degraded in a two-step proteolytic pathway known as regulated intramembrane proteolysis (RIP), thereby inactivating the cascade. The second step in this proteolytic pathway involves the zinc metalloprotease YaeL; V. cholerae cells lacking YaeL accumulate a truncated yet active form of TcpP termed TcpP*. We hypothesized that a protease acting prior to YaeL degrades TcpP to TcpP*, which is the substrate of YaeL. In this study, we demonstrate that a C-terminal protease called Tsp degrades TcpP to form TcpP*, which is then acted upon by YaeL. We present evidence that TcpH and Tsp serve to protect full-length TcpP from spurious proteolysis by YaeL. Cleavage by Tsp occurs in the periplasmic domain of TcpP and requires residues TcpPA172 and TcpPI174 for wild-type activity.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Teoh
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo, Toledo, OH, 43614, USA.
authors.forename: Jyl S
authors.initials: JS
authors.lastname: Matson
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: DiRita
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D019897:Periplasm / Q000378:metabolism; D059748:Proteolysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014734:Vibrio cholerae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C097244:TCPP protein, Vibrio cholerae; D014157:Transcription Factors; D010450:Endopeptidases; C072135:C-terminal processing peptidase