title: The cofilin phosphatase slingshot homolog 1 (SSH1) links NOD1 signaling to actin remodeling.
abstract: NOD1 is an intracellular pathogen recognition receptor that contributes to anti-bacterial innate immune responses, adaptive immunity and tissue homeostasis. NOD1-induced signaling relies on actin remodeling, however, the details of the connection of NOD1 and the actin cytoskeleton remained elusive. Here, we identified in a druggable-genome wide siRNA screen the cofilin phosphatase SSH1 as a specific and essential component of the NOD1 pathway. We show that depletion of SSH1 impaired pathogen induced NOD1 signaling evident from diminished NF-κB activation and cytokine release. Chemical inhibition of actin polymerization using cytochalasin D rescued the loss of SSH1. We further demonstrate that NOD1 directly interacted with SSH1 at F-actin rich sites. Finally, we show that enhanced cofilin activity is intimately linked to NOD1 signaling. Our data thus provide evidence that NOD1 requires the SSH1/cofilin network for signaling and to detect bacterial induced changes in actin dynamics leading to NF-κB activation and innate immune responses.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Bielig
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lautz
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany; Steinbeis-Innovationszentrum Center for Systems Biomedicine, Falkensee, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Braun
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany.
authors.forename: Maureen
authors.initials: M
authors.lastname: Menning
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Machuy
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Brügmann
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Barisic
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Eisler
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Andree
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Zurek
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany.
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France; INSERM U786, Institut Pasteur, Paris, France; Microbiologie et Maladies Infectieuses, Collège de France, Paris, France.
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Hausser
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany; University of Hohenheim, Institute of Nutritional Medicine, Stuttgart, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kufer
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism*; D004405:Dysentery, Bacillary / Q000382:microbiology*; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012763:Shigella flexneri / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D000199:Actins; D051338:Cofilin 1; D018836:Inflammation Mediators; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human