A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

作者：Cheallaigh Cliona Ni^*; Sheedy Frederick J; Harris James; Munoz Wolf Natalia; Lee Jinhee; West Kim; McDermott Eva Palsson; Smyth Alicia; Gleeson Laura E; Coleman Michelle; Martinez Nuria; Hearnden Claire H A; Tynan Graham A; Carroll Elizabeth C; Jones Sarah A; Corr Sinead C; Bernard Nicholas J; Hughes Mark M; Corcoran Sarah E; O'Sullivan Mary; Fallon Ciara M; Kornfeld Hardy; Golenbock Douglas; Gordon Stephen V; O'Neill Luke A J; Lavelle Ed C^*

来源：Immunity, 2016, 44(2): 368-379.

DOI：10.1016/j.immuni.2016.01.019

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-g 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.

• 出版日期2016-2-16