A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

Abstract

SummaryHumans 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.

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

“…This is in line with observations of this cytokine's important role in the immune response to Mtb, with IL-12 receptor β1 deficiency recognised as the most common form of Mendelian susceptibility to mycobacterial infection [144]. Interestingly, we have recently described a role for the MyD88-adaptor-like (Mal) signalling protein in INF-γ signalling within the macrophage [145]. Mal activity is abrogated by a single nucleotide polymorphism at position S180 in its coding gene, and homozygosity for this SNP confers increased susceptibility to Mtb infection [146].…”

Current prospects of type II interferon γ signaling and autoimmunity

“…Furthermore, in a mouse model of encephalitis, the activation of Stat1-dependent and Stat1-independent pathways advanced IFN␥-induced reduction of myelin sheath thickness in the CNS despite Stat1 knockdown (26). Apparently, initiation of these alternative signaling pathways starts at the JAK activation sites in IFNGR1 with the recruitment of adaptor molecules such as MyD88 adaptor-like (Mal) (27) or the Fyn kinase (28). MAL is encoded by the gene Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP).…”

“…Noticeably, Mal-dependent IFNGR signaling required phosphorylation of the mitogen-activated protein kinases (MAPK) p38, not Stat1, for phagosome maturation and killing of intracellular infectious organisms such as Mycobacterium tuberculosis. Moreover, defects in the Mal-dependent IFN␥-signaling pathway due to non-synonymous single nucleotide polymorphism at S180L in the human TIRAP gene explains best the increased susceptibility of SLE patients for mycobacterial and pneumococcal infections (27). Similarly, recruitment of the Src kinase Fyn results in the formation of a complex that allows IFN␥ to activate Stat5b via PI3K signaling (29).…”

Enhanced mitochondrial pyruvate transport elicits a robust ROS production to sensitize the antitumor efficacy of interferon-γ in colon cancer

“…However, clinical use of IFNγ to treat tumors has failed due to severe side effects and its relative inefficacy [4] , [5] . Prior studies on tumor cell escape from IFNγ-mediated immune-surveillance focused on mutations in the IFNγ receptor IFNGR or the transcription factor STAT1 [6] , [7] , [8] , [9] . Few studies have elucidated the mechanism by which IFNγ mediates changes in the epigenetic or transcriptomic landscape in tumor cells [8] , [10] .…”