A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling
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Authors
Ní Cheallaigh, ClíonaLee, Jinhee
West, Kim
Martinez, Nuria
Kornfeld, Hardy
Golenbock, Douglas T.
Lavelle, Ed C.
UMass Chan Affiliations
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care MedicineDepartment of Medicine, Division of Infectious Diseases and Immunology
Document Type
Journal ArticlePublication Date
2016-02-16Keywords
Mal; TIRAP; autophagy; interferon gamma; phagolysosome maturation; tuberculosisImmunity
Immunology of Infectious Disease
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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-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.Source
Immunity. 2016 Feb 16;44(2):368-79. doi: 10.1016/j.immuni.2016.01.019. Link to article on publisher's siteDOI
10.1016/j.immuni.2016.01.019Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39939PubMed ID
26885859Notes
Full author list omitted for brevity. For full list of authors see article.
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Copyright © 2016 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.immuni.2016.01.019
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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>