Ní Cheallaigh Clíona, Sheedy Frederick J, Harris James, Muñoz-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 Sinéad 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, Keane Joseph
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland; Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland.
Immunity. 2016 Feb 16;44(2):368-79. 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-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.
Toll样受体（TLR）衔接蛋白Mal（由TIRAP编码）常见S180L多态性的杂合人类对包括结核病（TB）在内的多种传染病具有抵抗力，而该等位基因的纯合人类患病风险增加。这种易感性差异的原因尚不清楚。我们报告称，Mal在干扰素-γ（IFN-γ）受体信号传导中具有不依赖TLR的作用。依赖Mal的IFN-γ受体（IFNGR）信号传导导致丝裂原活化蛋白激酶（MAPK）p38磷酸化和自噬。通过Mal的IFN-γ信号传导是吞噬体成熟和杀灭细胞内结核分枝杆菌（Mtb）所必需的。S180L多态性及其小鼠等效物S200L降低了Mal对IFNGR的亲和力，从而损害巨噬细胞中的IFNGR信号传导并削弱对TB的反应。我们的研究结果突出了Mal在TLR系统之外的作用，并暗示TIRAP中的基因变异可能与包括自身免疫和癌症在内的其他IFN-γ相关疾病有关。
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