title: Cycle inhibiting factors (CIFs) are a growing family of functional cyclomodulins present in invertebrate and mammal bacterial pathogens.
abstract: The cycle inhibiting factor (Cif) produced by enteropathogenic and enterohemorrhagic Escherichia coli was the first cyclomodulin to be identified that is injected into host cells via the type III secretion machinery. Cif provokes cytopathic effects characterized by G(1) and G(2) cell cycle arrests, accumulation of the cyclin-dependent kinase inhibitors (CKIs) p21(waf1/cip1) and p27(kip1) and formation of actin stress fibres. The X-ray crystal structure of Cif revealed it to be a divergent member of a superfamily of enzymes including cysteine proteases and acetyltransferases that share a conserved catalytic triad. Here we report the discovery and characterization of four Cif homologs encoded by different pathogenic or symbiotic bacteria isolated from vertebrates or invertebrates. Cif homologs from the enterobacteria Yersinia pseudotuberculosis, Photorhabdus luminescens, Photorhabdus asymbiotica and the beta-proteobacterium Burkholderia pseudomallei all induce cytopathic effects identical to those observed with Cif from pathogenic E. coli. Although these Cif homologs are remarkably divergent in primary sequence, the catalytic triad is strictly conserved and was shown to be crucial for cell cycle arrest, cytoskeleton reorganization and CKIs accumulation. These results reveal that Cif proteins form a growing family of cyclomodulins in bacteria that interact with very distinct hosts including insects, nematodes and humans.
authors.affiliation: INRA, UMR1225, Toulouse, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Jubelin
authors.forename: Carolina Varela
authors.initials: CV
authors.lastname: Chavez
authors.forename: Frédéric
authors.initials: F
authors.lastname: Taieb
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Banfield
authors.forename: Ascel
authors.initials: A
authors.lastname: Samba-Louaka
authors.forename: Rika
authors.initials: R
authors.lastname: Nobe
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Nougayrède
authors.forename: Robert
authors.initials: R
authors.lastname: Zumbihl
authors.forename: Alain
authors.initials: A
authors.lastname: Givaudan
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Escoubas
authors.forename: Eric
authors.initials: E
authors.lastname: Oswald
mesh_terms: D000818:Animals; D001419:Bacteria / Q000472:pathogenicity*; D001426:Bacterial Proteins / Q000502:physiology*; D002453:Cell Cycle; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004754:Enterobacter / Q000737:chemistry* / Q000472:pathogenicity; D029968:Escherichia coli Proteins; D007399:Interphase; D017386:Sequence Homology, Amino Acid
chemical_list: D001426:Bacterial Proteins; C481998:Cif protein, E coli; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D029968:Escherichia coli Proteins