STING Recognition of Cytoplasmic DNA Instigates Cellular Defense

Takayuki Abe; Ai Harashima; Tianli Xia; Hiroyasu Konno; Keiko Konno; Alejo Morales; Jeonghyun Ahn; Delia Gutman; Glen N. Barber

doi:10.1016/j.molcel.2013.01.039

STING Recognition of Cytoplasmic DNA Instigates Cellular Defense

Takayuki Abe, Ai Harashima, Tianli Xia, Hiroyasu Konno, Keiko Konno, Alejo Morales, Jeonghyun Ahn, Delia Gutman, Glen N. Barber

Cell Biology

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

153 Scopus citations

Abstract

How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and proinflammatory genes in addition to type I IFN. Our data indicate that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.

Original language	English (US)
Pages (from-to)	5-15
Number of pages	11
Journal	Molecular Cell
Volume	50
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2013.01.039
State	Published - Apr 11 2013

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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title = "STING Recognition of Cytoplasmic DNA Instigates Cellular Defense",

abstract = "How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and proinflammatory genes in addition to type I IFN. Our data indicate that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.",

author = "Takayuki Abe and Ai Harashima and Tianli Xia and Hiroyasu Konno and Keiko Konno and Alejo Morales and Jeonghyun Ahn and Delia Gutman and Barber, {Glen N.}",

note = "Funding Information: We thank David Levy for Stat1 −/− MEFs, David Leib for HSV-Luc, Vladlen Slepak for BIAcore analysis, Arun Malhotra for assistance with purification, Arabela Grigorescu for FP analysis, Biju Issac and Daria Salyakina for gene array analysis, and George McNamara for technical assistance. This work was funded in part by grants R01AI079336 and UO1AI083015. A.H., T.A., and T.X. carried out most of the experiments, D.G. assisted in DNA binding analysis, T.X. and A.M. performed DNA array and STING-dependent gene analysis, H.K. carried out STING dimerization and trafficking analysis, and K.K. purified STING. J.A. did HSV studies. G.N.B. wrote the manuscript. ",

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AU - Abe, Takayuki

AU - Harashima, Ai

AU - Xia, Tianli

AU - Konno, Hiroyasu

AU - Konno, Keiko

AU - Morales, Alejo

AU - Ahn, Jeonghyun

AU - Gutman, Delia

AU - Barber, Glen N.

N1 - Funding Information: We thank David Levy for Stat1 −/− MEFs, David Leib for HSV-Luc, Vladlen Slepak for BIAcore analysis, Arun Malhotra for assistance with purification, Arabela Grigorescu for FP analysis, Biju Issac and Daria Salyakina for gene array analysis, and George McNamara for technical assistance. This work was funded in part by grants R01AI079336 and UO1AI083015. A.H., T.A., and T.X. carried out most of the experiments, D.G. assisted in DNA binding analysis, T.X. and A.M. performed DNA array and STING-dependent gene analysis, H.K. carried out STING dimerization and trafficking analysis, and K.K. purified STING. J.A. did HSV studies. G.N.B. wrote the manuscript.

PY - 2013/4/11

Y1 - 2013/4/11

N2 - How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and proinflammatory genes in addition to type I IFN. Our data indicate that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.

AB - How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and proinflammatory genes in addition to type I IFN. Our data indicate that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.

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