A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

Summary

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.

Graphical Abstract

Highlights

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  Mal has a TLR-independent role in IFNGR signaling

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  IFNGR signaling via Mal leads to p38 phosphorylation, autophagy, and killing of TB

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  The S180L mutation attenuates responses to IFN-γ stimulation

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  S180L mutations impair in vitro and in vivo responses to TB

Abstract

Mal (encoded by TIRAP) is a signaling adaptor in the TLR pathway. Ní Cheallaigh and colleagues demonstrate an additional role for Mal in IFN-γ signaling and find that it is required to kill intracellular M. tuberculosis. The common human Mal S180L polymorphism attenuates IFN-γ signaling and impairs responses to tuberculosis infection.