title: Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense.
abstract: Obligate intracellularChlamydia trachomatisreplicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl-1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity ofC. trachomatisfor IFNγ and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense.
authors.affiliation: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Annette
authors.identifier: 0000-0002-3979-9396
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Molecular Biosciences, University of Kansas, lawrence, United States.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Harrison
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Yesid
authors.initials: Y
authors.lastname: Ramirez
authors.affiliation: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Auer
authors.affiliation: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Suvagata Roy
authors.initials: SR
authors.lastname: Chowdhury
authors.affiliation: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Bhupesh K
authors.identifier: 0000-0001-7051-4670
authors.initials: BK
authors.lastname: Prusty
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Sauer
authors.affiliation: Department of Molecular Biosciences, University of Kansas, lawrence, United States.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Dimond
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
authors.affiliation: Department of Molecular Biosciences, University of Kansas, lawrence, United States.
authors.forename: P Scott
authors.initials: PS
authors.lastname: Hefty
authors.affiliation: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.identifier: 0000-0003-4740-6991
authors.initials: T
authors.lastname: Rudel
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D002692:Chlamydia trachomatis / Q000276:immunology* / Q000502:physiology*; D000072017:Deubiquitinating Enzymes / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D014617:Vacuoles / Q000382:microbiology*
chemical_list: D001426:Bacterial Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000072017:Deubiquitinating Enzymes
keywords: Chlamydia trachomatis; Mcl-1; cell biology; cell-autonomous defense; deubiquitinase; infectious disease; microbiology