title: A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling.
abstract: Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland; Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland. Electronic address: nicheacm@tcd.ie.
authors.forename: Clíona
authors.initials: C
authors.lastname: Ní Cheallaigh
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.affiliation: Centre for Inflammatory Diseases, Southern Clinical School, Monash University Faculty of Medicine, Nursing and Health Sciences, Clayton, Victoria 3168, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.affiliation: Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Muñoz-Wolf
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: West
authors.affiliation: Inflammation Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Eva Palsson
authors.initials: EP
authors.lastname: McDermott
authors.affiliation: UCD Schools of Veterinary Medicine, Medicine and Medical Science, and Biomolecular and Biomedical Science, and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Alicia
authors.initials: A
authors.lastname: Smyth
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Gleeson
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Coleman
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Nuria
authors.initials: N
authors.lastname: Martinez
authors.affiliation: Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Claire H A
authors.initials: CH
authors.lastname: Hearnden
authors.affiliation: Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Tynan
authors.affiliation: Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Carroll
authors.affiliation: Centre for Inflammatory Diseases, Southern Clinical School, Monash University Faculty of Medicine, Nursing and Health Sciences, Clayton, Victoria 3168, Australia.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Inflammation Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Sinéad C
authors.initials: SC
authors.lastname: Corr
authors.affiliation: Inflammation Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bernard
authors.affiliation: Inflammation Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Hughes
authors.affiliation: Inflammation Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Corcoran
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Sullivan
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland.
authors.forename: Ciara M
authors.initials: CM
authors.lastname: Fallon
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Golenbock
authors.affiliation: UCD Schools of Veterinary Medicine, Medicine and Medical Science, and Biomolecular and Biomedical Science, and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Gordon
authors.affiliation: Inflammation Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.affiliation: Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland; Advanced Materials and BioEngineering Research (AMBER), Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College, D02 PN40, Dublin, Ireland. Electronic address: lavellee@tcd.ie.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Keane
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008264:Macrophages / Q000382:microbiology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017471:Receptors, Interferon / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D017471:Receptors, Interferon; D017472:Receptors, Interleukin-1; D000096743:Interferon gamma Receptor; C499045:TIRAP protein, mouse
keywords: Mal; TIRAP; autophagy; interferon gamma; phagolysosome maturation; tuberculosis