A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

Clíona Ní Cheallaigh; Frederick J. Sheedy; James Harris; Natalia Muñoz-Wolf; Jinhee Lee; Kim West; Eva Palsson McDermott; Alicia Smyth; Laura E. Gleeson; Michelle Coleman; Nuria Martinez; Claire H.A. Hearnden; Graham A. Tynan; Elizabeth C. Carroll; Sarah A. Jones; Sinéad C. Corr; Nicholas J. Bernard; Mark M. Hughes; Sarah E. Corcoran; Mary O'Sullivan; Ciara M. Fallon; Hardy Kornfeld; Douglas Golenbock; Stephen V. Gordon; Luke A.J. O'Neill; Ed C. Lavelle; Joseph Keane

doi:10.1016/j.immuni.2016.01.019

A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

Clíona Ní Cheallaigh
, Frederick J. Sheedy
, James Harris
, Natalia Muñoz-Wolf
, Jinhee Lee
, Kim West
, Eva Palsson McDermott
, Alicia Smyth
, Laura E. Gleeson
, Michelle Coleman
, Nuria Martinez
, Claire H.A. Hearnden
, Graham A. Tynan
, Elizabeth C. Carroll
, Sarah A. Jones
, Sinéad C. Corr
, Nicholas J. Bernard
, Mark M. Hughes
, Sarah E. Corcoran
, Mary O'Sullivan

Ciara M. Fallon, Hardy Kornfeld, Douglas Golenbock, Stephen V. Gordon, Luke A.J. O'Neill, Ed C. Lavelle, Joseph Keane

St James's Hospital
Trinity College Dublin
Monash University
University of Massachusetts Medical School
University College Dublin

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	368-379
Number of pages	12
Journal	Immunity
Volume	44
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2016.01.019
Publication status	Published - 16 Feb 2016
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Autophagy
Interferon gamma
Mal
Phagolysosome maturation
TIRAP
Tuberculosis

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10.1016/j.immuni.2016.01.019

Cite this

Ní Cheallaigh, C., Sheedy, F. J., Harris, J., Muñoz-Wolf, N., Lee, J., West, K., McDermott, E. P., Smyth, A., Gleeson, L. E., Coleman, M., Martinez, N., Hearnden, C. H. A., Tynan, G. A., Carroll, E. C., Jones, S. A., Corr, S. C., Bernard, N. J., Hughes, M. M., Corcoran, S. E., ... Keane, J. (2016). A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling. Immunity, 44(2), 368-379. https://doi.org/10.1016/j.immuni.2016.01.019

@article{0cf183a7775745bb9487b8474d37697b,

title = "A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling",

abstract = "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.",

keywords = "Autophagy, Interferon gamma, Mal, Phagolysosome maturation, TIRAP, Tuberculosis",

author = "\{N{\'i} Cheallaigh\}, Cl{\'i}ona and Sheedy, \{Frederick J.\} and James Harris and Natalia Mu{\~n}oz-Wolf and Jinhee Lee and Kim West and McDermott, \{Eva Palsson\} and Alicia Smyth and Gleeson, \{Laura E.\} and Michelle Coleman and Nuria Martinez and Hearnden, \{Claire H.A.\} and Tynan, \{Graham A.\} and Carroll, \{Elizabeth C.\} and Jones, \{Sarah A.\} and Corr, \{Sin{\'e}ad C.\} and Bernard, \{Nicholas J.\} and Hughes, \{Mark M.\} and Corcoran, \{Sarah E.\} and Mary O'Sullivan and Fallon, \{Ciara M.\} and Hardy Kornfeld and Douglas Golenbock and Gordon, \{Stephen V.\} and O'Neill, \{Luke A.J.\} and Lavelle, \{Ed C.\} and Joseph Keane",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2016",

month = feb,

day = "16",

doi = "10.1016/j.immuni.2016.01.019",

language = "English",

volume = "44",

pages = "368--379",

journal = "Immunity",

issn = "1074-7613",

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}

Ní Cheallaigh, C, Sheedy, FJ, Harris, J, Muñoz-Wolf, N, Lee, J, West, K, McDermott, EP, Smyth, A, Gleeson, LE, Coleman, M, Martinez, N, Hearnden, CHA, Tynan, GA, Carroll, EC, Jones, SA, Corr, SC, Bernard, NJ, Hughes, MM, Corcoran, SE, O'Sullivan, M, Fallon, CM, Kornfeld, H, Golenbock, D, Gordon, SV, O'Neill, LAJ, Lavelle, EC & Keane, J 2016, 'A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling', Immunity, vol. 44, no. 2, pp. 368-379. https://doi.org/10.1016/j.immuni.2016.01.019

TY - JOUR

T1 - A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

AU - Ní Cheallaigh, Clíona

AU - Sheedy, Frederick J.

AU - Harris, James

AU - Muñoz-Wolf, Natalia

AU - Lee, Jinhee

AU - West, Kim

AU - McDermott, Eva Palsson

AU - Smyth, Alicia

AU - Gleeson, Laura E.

AU - Coleman, Michelle

AU - Martinez, Nuria

AU - Hearnden, Claire H.A.

AU - Tynan, Graham A.

AU - Carroll, Elizabeth C.

AU - Jones, Sarah A.

AU - Corr, Sinéad C.

AU - Bernard, Nicholas J.

AU - Hughes, Mark M.

AU - Corcoran, Sarah E.

AU - O'Sullivan, Mary

AU - Fallon, Ciara M.

AU - Kornfeld, Hardy

AU - Golenbock, Douglas

AU - Gordon, Stephen V.

AU - O'Neill, Luke A.J.

AU - Lavelle, Ed C.

AU - Keane, Joseph

PY - 2016/2/16

Y1 - 2016/2/16

N2 - 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.

AB - 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.

KW - Autophagy

KW - Interferon gamma

KW - Mal

KW - Phagolysosome maturation

KW - TIRAP

KW - Tuberculosis

UR - https://www.scopus.com/pages/publications/84958621412

U2 - 10.1016/j.immuni.2016.01.019

DO - 10.1016/j.immuni.2016.01.019

M3 - Article

C2 - 26885859

AN - SCOPUS:84958621412

SN - 1074-7613

VL - 44

SP - 368

EP - 379

JO - Immunity

JF - Immunity

IS - 2

ER -

A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling

Abstract

UN SDGs

Keywords

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