A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

被引：25

作者：

Cheallaigh, Cliona Ni ^{[1
,2
,3
]}

Sheedy, Frederick J. ^{[1
,2
]}

Harris, James ^{[4
]}

Munoz-Wolf, Natalia ^{[3
]}

Lee, Jinhee ^{[5
]}

West, Kim ^{[5
]}

McDermott, Eva Palsson ^{[6
]}

Smyth, Alicia ^{[7
,8
,9
,10
]}

Gleeson, Laura E. ^{[1
,2
]}

Coleman, Michelle ^{[1
,2
]}

Martinez, Nuria ^{[5
]}

Hearnden, Claire H. A. ^{[3
]}

Tynan, Graham A. ^{[3
]}

Carroll, Elizabeth C. ^{[3
]}

Jones, Sarah A. ^{[4
]}

Corr, Sinead C. ^{[6
]}

Bernard, Nicholas J. ^{[6
]}

Hughes, Mark M. ^{[6
]}

Corcoran, Sarah E. ^{[6
]}

O'Sullivan, Mary ^{[1
,2
]}

Fallon, Ciara M. ^{[1
,2
]}

Kornfeld, Hardy ^{[5
]}

Golenbock, Douglas ^{[5
]}

Gordon, Stephen V. ^{[7
,8
,9
,10
]}

O'Neill, Luke A. J. ^{[6
]}

Lavelle, Ed C. ^{[3
,11
]}

Keane, Joseph ^{[1
,2
]}

机构：

[1] Univ Dublin Trinity Coll, Dept Clin Med, Inst Mol Med, D08 W9RT, Dublin 2, Ireland

[2] St James Hosp, D08 W9RT, Dublin 8, Ireland

[3] Univ Dublin Trinity Coll, Adjuvant Res Grp, Sch Biochem & Immunol, Trinity Biomed Sci Inst, D02 PN40, Dublin 2, Ireland

[4] Monash Univ, Fac Med Nursing & Hlth Sci, Southern Clin Sch, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia

[5] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA

[6] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Inflammat Res Grp, D02 PN40, Dublin 2, Ireland

[7] Univ Coll Dublin, UCD Sch Vet Med, Dublin 4, Ireland

[8] Univ Coll Dublin, UCD Sch Med & Med Sci, Dublin 4, Ireland

[9] Univ Coll Dublin, UCD Sch Biomol & Biomol Sci, Dublin 4, Ireland

[10] Univ Coll Dublin, UCD Conway Inst, Dublin 4, Ireland

[11] Univ Dublin Trinity Coll, Adv Mat & BioEngn Res AMBER, CRANN, D02 PN40, Dublin, Ireland

来源：

IMMUNITY | 2016年 / 44卷 / 02期

基金：

爱尔兰科学基金会; 英国惠康基金;

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; MYCOBACTERIUM-TUBERCULOSIS INFECTION; TOLL-LIKE RECEPTORS; CD8(+) T-CELLS; IFN-GAMMA; DEFENSE-MECHANISM; MACROPHAGES; TIRAP; AUTOPHAGY; IMMUNITY;

D O I：

10.1016/j.immuni.2016.01.019

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：368 / 379

页数：12

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