A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling
AuthorsNí Cheallaigh, Clíona
Golenbock, Douglas T.
Lavelle, Ed C.
UMass Chan AffiliationsDepartment of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine
Department of Medicine, Division of Infectious Diseases and Immunology
KeywordsMal; TIRAP; autophagy; interferon gamma; phagolysosome maturation; tuberculosis
Immunology of Infectious Disease
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AbstractHumans 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-gamma) receptor signaling. Mal-dependent IFN-gamma receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-gamma 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-gamma-related diseases including autoimmunity and cancer.
SourceImmunity. 2016 Feb 16;44(2):368-79. doi: 10.1016/j.immuni.2016.01.019. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/39939
Full author list omitted for brevity. For full list of authors see article.
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RightsCopyright © 2016 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as Copyright © 2016 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</p>