Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells

Fabio R. Santori; Pengxiang Huang; Serge A. Van De Pavert; Eugene F. Douglass; David J. Leaver; Brad A. Haubrich; Rok Keber; Gregor Lorbek; Tanja Konijn; Brittany N. Rosales; Damjana Rozman; Simon Horvat; Alain Rahier; Reina E. Mebius; Fraydoon Rastinejad; W. David Nes; Dan R. Littman

doi:10.1016/j.cmet.2015.01.004

Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells

Fabio R. Santori, Pengxiang Huang, Serge A. Van De Pavert, Eugene F. Douglass, David J. Leaver, Brad A. Haubrich, Rok Keber, Gregor Lorbek, Tanja Konijn, Brittany N. Rosales, Damjana Rozman, Simon Horvat, Alain Rahier, Reina E. Mebius, Fraydoon Rastinejad, W. David Nes, Dan R. Littman

Chemistry and Biochemistry

Research output: Contribution to journal › Article

106 Scopus citations

Abstract

Summary Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.

Original language	English
Pages (from-to)	286-298
Number of pages	13
Journal	Cell Metabolism
Volume	21
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2015.01.004
State	Published - Feb 3 2015

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Santori, F. R., Huang, P., Van De Pavert, S. A., Douglass, E. F., Leaver, D. J., Haubrich, B. A., Keber, R., Lorbek, G., Konijn, T., Rosales, B. N., Rozman, D., Horvat, S., Rahier, A., Mebius, R. E., Rastinejad, F., Nes, W. D., & Littman, D. R. (2015). Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells. Cell Metabolism, 21(2), 286-298. https://doi.org/10.1016/j.cmet.2015.01.004

Santori, Fabio R. ; Huang, Pengxiang ; Van De Pavert, Serge A. ; Douglass, Eugene F. ; Leaver, David J. ; Haubrich, Brad A. ; Keber, Rok ; Lorbek, Gregor ; Konijn, Tanja ; Rosales, Brittany N. ; Rozman, Damjana ; Horvat, Simon ; Rahier, Alain ; Mebius, Reina E. ; Rastinejad, Fraydoon ; Nes, W. David ; Littman, Dan R. / Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells. In: Cell Metabolism. 2015 ; Vol. 21, No. 2. pp. 286-298.

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title = "Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells",

abstract = "Summary Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.",

author = "Santori, {Fabio R.} and Pengxiang Huang and {Van De Pavert}, {Serge A.} and Douglass, {Eugene F.} and Leaver, {David J.} and Haubrich, {Brad A.} and Rok Keber and Gregor Lorbek and Tanja Konijn and Rosales, {Brittany N.} and Damjana Rozman and Simon Horvat and Alain Rahier and Mebius, {Reina E.} and Fraydoon Rastinejad and Nes, {W. David} and Littman, {Dan R.}",

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doi = "10.1016/j.cmet.2015.01.004",

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Santori, FR, Huang, P, Van De Pavert, SA, Douglass, EF, Leaver, DJ, Haubrich, BA, Keber, R, Lorbek, G, Konijn, T, Rosales, BN, Rozman, D, Horvat, S, Rahier, A, Mebius, RE, Rastinejad, F, Nes, WD & Littman, DR 2015, 'Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells', Cell Metabolism, vol. 21, no. 2, pp. 286-298. https://doi.org/10.1016/j.cmet.2015.01.004

Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells. / Santori, Fabio R.; Huang, Pengxiang; Van De Pavert, Serge A.; Douglass, Eugene F.; Leaver, David J.; Haubrich, Brad A.; Keber, Rok; Lorbek, Gregor; Konijn, Tanja; Rosales, Brittany N.; Rozman, Damjana; Horvat, Simon; Rahier, Alain; Mebius, Reina E.; Rastinejad, Fraydoon; Nes, W. David; Littman, Dan R.

In: Cell Metabolism, Vol. 21, No. 2, 03.02.2015, p. 286-298.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells

AU - Santori, Fabio R.

AU - Huang, Pengxiang

AU - Van De Pavert, Serge A.

AU - Douglass, Eugene F.

AU - Leaver, David J.

AU - Haubrich, Brad A.

AU - Keber, Rok

AU - Lorbek, Gregor

AU - Konijn, Tanja

AU - Rosales, Brittany N.

AU - Rozman, Damjana

AU - Horvat, Simon

AU - Rahier, Alain

AU - Mebius, Reina E.

AU - Rastinejad, Fraydoon

AU - Nes, W. David

AU - Littman, Dan R.

PY - 2015/2/3

Y1 - 2015/2/3

N2 - Summary Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.

AB - Summary Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.

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DO - 10.1016/j.cmet.2015.01.004

M3 - Article

C2 - 25651181

AN - SCOPUS:84922901154

VL - 21

SP - 286

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JO - Cell Metabolism

JF - Cell Metabolism

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IS - 2

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