TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages

Yang Li, Sharmy J. James, David H. Wyllie, Claire Wynne, A. Czibula, Ahmed Bukhari, Katherine Pye, Seri Musfirah Bte Mustafah, R. Fajka-Boja, Eniko Szabo, Adrienn Angyal, Z. Hegedűs, Laszlo Kovacs, Adrian V.S. Hill, Caroline A. Jefferies, Heather L. Wilson, Zhang Yongliang, Endre Kiss-Toth

Research output: Contribution to journalArticle

Abstract

Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMP-induced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases.

Original languageEnglish
Pages (from-to)16479-16488
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number33
DOIs
Publication statusPublished - Aug 13 2019

Fingerprint

Macrophages
Genes
Interferon Type I
Messenger RNA
Complement C3
Proteins
Innate Immunity
Systemic Lupus Erythematosus
Transcriptional Activation
Complement System Proteins
Chronic Disease
Transcription Factors
Phosphotransferases
T-Lymphocytes
Serum
Therapeutics

Keywords

  • Interferon signaling
  • Lupus
  • STIM1
  • STING
  • TMEM203

ASJC Scopus subject areas

  • General

Cite this

TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages. / Li, Yang; James, Sharmy J.; Wyllie, David H.; Wynne, Claire; Czibula, A.; Bukhari, Ahmed; Pye, Katherine; Bte Mustafah, Seri Musfirah; Fajka-Boja, R.; Szabo, Eniko; Angyal, Adrienn; Hegedűs, Z.; Kovacs, Laszlo; Hill, Adrian V.S.; Jefferies, Caroline A.; Wilson, Heather L.; Yongliang, Zhang; Kiss-Toth, Endre.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 33, 13.08.2019, p. 16479-16488.

Research output: Contribution to journalArticle

Li, Y, James, SJ, Wyllie, DH, Wynne, C, Czibula, A, Bukhari, A, Pye, K, Bte Mustafah, SM, Fajka-Boja, R, Szabo, E, Angyal, A, Hegedűs, Z, Kovacs, L, Hill, AVS, Jefferies, CA, Wilson, HL, Yongliang, Z & Kiss-Toth, E 2019, 'TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 33, pp. 16479-16488. https://doi.org/10.1073/pnas.1901090116
Li, Yang ; James, Sharmy J. ; Wyllie, David H. ; Wynne, Claire ; Czibula, A. ; Bukhari, Ahmed ; Pye, Katherine ; Bte Mustafah, Seri Musfirah ; Fajka-Boja, R. ; Szabo, Eniko ; Angyal, Adrienn ; Hegedűs, Z. ; Kovacs, Laszlo ; Hill, Adrian V.S. ; Jefferies, Caroline A. ; Wilson, Heather L. ; Yongliang, Zhang ; Kiss-Toth, Endre. / TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 33. pp. 16479-16488.
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abstract = "Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMP-induced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases.",
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AU - Angyal, Adrienn

AU - Hegedűs, Z.

AU - Kovacs, Laszlo

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N2 - Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMP-induced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases.

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