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: Clíona Ní Cheallaigh, Frederick J Sheedy, James Harris, Natalia Muñoz-Wolf, Jinhee Lee, Kim West, Eva Palsson McDermott, Alicia Smyth, Laura E Gleeson, Michelle Coleman, Nuria Martinez, Claire H A Hearnden, Graham A Tynan, Elizabeth C Carroll, Sarah A Jones, Sinéad C Corr, Nicholas J Bernard, Mark M Hughes, Sarah E Corcoran, Mary O'Sullivan, Ciara M Fallon, Hardy Kornfeld, Douglas Golenbock, Stephen V Gordon, Luke A J O'Neill, Ed C Lavelle, Joseph Keane
• Journal: Immunity (Immunity) Vol. 44 Issue 2 Pg. 368-79 (Feb 16 2016) ISSN: 1097-4180 [Electronic] United States
• PMID: 26885859 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Glycoproteins
• RNA, Small Interfering
• Receptors, Interferon
• Receptors, Interleukin-1
• TIRAP protein, mouse
• interferon gamma receptor
• Interferon-gamma

Topics

• Animals
• Autophagy (genetics)
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genotype
• HEK293 Cells
• Humans
• Immunity, Innate (genetics)
• Interferon-gamma (metabolism)
• MAP Kinase Signaling System (genetics)
• Macrophages (microbiology, physiology)
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Mycobacterium tuberculosis (immunology)
• Polymorphism, Genetic
• Protein Binding (genetics)
• RNA, Small Interfering (genetics)
• Receptors, Interferon (metabolism)
• Receptors, Interleukin-1 (genetics, metabolism)
• Tuberculosis, Pulmonary (genetics, immunology)