STEEP mediates STING ER exit and activation of signaling

Bao cun Zhang; Ramya Nandakumar; Line S. Reinert; Jinrong Huang; Anders Laustsen; Zong liang Gao; Cheng long Sun; Søren Beck Jensen; Anne Troldborg; Sonia Assil; Martin F. Berthelsen; Carsten Scavenius; Yan Zhang; Samuel J. Windross; David Olagnier; Thaneas Prabakaran; Chiranjeevi Bodda; Ryo Narita; Yujia Cai; Cong gang Zhang; Harald Stenmark; Christine M. Doucet; Takeshi Noda; Zheng Guo; Raphaela Goldbach-Mansky; Rune Hartmann; Zhijian J. Chen; Jan J. Enghild; Rasmus O. Bak; Martin K. Thomsen; Søren R. Paludan

doi:10.1038/s41590-020-0730-5

STEEP mediates STING ER exit and activation of signaling

Bao cun Zhang, Ramya Nandakumar, Line S. Reinert, Jinrong Huang, Anders Laustsen, Zong liang Gao, Cheng long Sun, Søren Beck Jensen, Anne Troldborg, Sonia Assil, Martin F. Berthelsen, Carsten Scavenius, Yan Zhang, Samuel J. Windross, David Olagnier, Thaneas Prabakaran, Chiranjeevi Bodda, Ryo Narita, Yujia Cai, Cong gang ZhangHarald Stenmark, Christine M. Doucet, Takeshi Noda, Zheng Guo, Raphaela Goldbach-Mansky, Rune Hartmann, Zhijian J. Chen, Jan J. Enghild, Rasmus O. Bak, Martin K. Thomsen, Søren R. Paludan

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

80 Scopus citations

Abstract

STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.

Original language	English (US)
Pages (from-to)	868-879
Number of pages	12
Journal	Nature immunology
Volume	21
Issue number	8
DOIs	https://doi.org/10.1038/s41590-020-0730-5
State	Published - Aug 1 2020

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Zhang, B. C., Nandakumar, R., Reinert, L. S., Huang, J., Laustsen, A., Gao, Z. L., Sun, C. L., Jensen, S. B., Troldborg, A., Assil, S., Berthelsen, M. F., Scavenius, C., Zhang, Y., Windross, S. J., Olagnier, D., Prabakaran, T., Bodda, C., Narita, R., Cai, Y., ... Paludan, S. R. (2020). STEEP mediates STING ER exit and activation of signaling. Nature immunology, 21(8), 868-879. https://doi.org/10.1038/s41590-020-0730-5

Zhang, BC, Nandakumar, R, Reinert, LS, Huang, J, Laustsen, A, Gao, ZL, Sun, CL, Jensen, SB, Troldborg, A, Assil, S, Berthelsen, MF, Scavenius, C, Zhang, Y, Windross, SJ, Olagnier, D, Prabakaran, T, Bodda, C, Narita, R, Cai, Y, Zhang, CG, Stenmark, H, Doucet, CM, Noda, T, Guo, Z, Goldbach-Mansky, R, Hartmann, R, Chen, ZJ, Enghild, JJ, Bak, RO, Thomsen, MK & Paludan, SR 2020, 'STEEP mediates STING ER exit and activation of signaling', Nature immunology, vol. 21, no. 8, pp. 868-879. https://doi.org/10.1038/s41590-020-0730-5

@article{a5f276e8678940b894f7b15fd81d6477,

title = "STEEP mediates STING ER exit and activation of signaling",

abstract = "STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.",

author = "Zhang, {Bao cun} and Ramya Nandakumar and Reinert, {Line S.} and Jinrong Huang and Anders Laustsen and Gao, {Zong liang} and Sun, {Cheng long} and Jensen, {S{\o}ren Beck} and Anne Troldborg and Sonia Assil and Berthelsen, {Martin F.} and Carsten Scavenius and Yan Zhang and Windross, {Samuel J.} and David Olagnier and Thaneas Prabakaran and Chiranjeevi Bodda and Ryo Narita and Yujia Cai and Zhang, {Cong gang} and Harald Stenmark and Doucet, {Christine M.} and Takeshi Noda and Zheng Guo and Raphaela Goldbach-Mansky and Rune Hartmann and Chen, {Zhijian J.} and Enghild, {Jan J.} and Bak, {Rasmus O.} and Thomsen, {Martin K.} and Paludan, {S{\o}ren R.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = aug,

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doi = "10.1038/s41590-020-0730-5",

language = "English (US)",

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T1 - STEEP mediates STING ER exit and activation of signaling

AU - Zhang, Bao cun

AU - Nandakumar, Ramya

AU - Reinert, Line S.

AU - Huang, Jinrong

AU - Laustsen, Anders

AU - Gao, Zong liang

AU - Sun, Cheng long

AU - Jensen, Søren Beck

AU - Troldborg, Anne

AU - Assil, Sonia

AU - Berthelsen, Martin F.

AU - Scavenius, Carsten

AU - Zhang, Yan

AU - Windross, Samuel J.

AU - Olagnier, David

AU - Prabakaran, Thaneas

AU - Bodda, Chiranjeevi

AU - Narita, Ryo

AU - Cai, Yujia

AU - Zhang, Cong gang

AU - Stenmark, Harald

AU - Doucet, Christine M.

AU - Noda, Takeshi

AU - Guo, Zheng

AU - Goldbach-Mansky, Raphaela

AU - Hartmann, Rune

AU - Chen, Zhijian J.

AU - Enghild, Jan J.

AU - Bak, Rasmus O.

AU - Thomsen, Martin K.

AU - Paludan, Søren R.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.

AB - STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.

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DO - 10.1038/s41590-020-0730-5

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AN - SCOPUS:85088253679

SN - 1529-2908

VL - 21

SP - 868

EP - 879

JO - Nature immunology

JF - Nature immunology

IS - 8

ER -

STEEP mediates STING ER exit and activation of signaling

Abstract

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