A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

Immunity
Clíona Ní CheallaighJoseph Keane

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.

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Citations

Jun 2, 2018·Biomolecular Concepts·Gunjan KakBrijendra K Tiwari
Feb 23, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jennifer K DowlingAshley Mansell
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Mar 7, 2021·Nature Communications·Jennifer K DowlingClaire E McCoy
Apr 4, 2021·International Journal of Molecular Sciences·Christina CahillJames J Phelan
Jul 13, 2019·Microbiology Spectrum·Jonathan Kevin Sia, Jyothi Rengarajan

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Methods Mentioned

BETA
co-immunoprecipitation
flow cytometry
ELISA

Software Mentioned

PicoQuant

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