Post-translational regulation of RORγt—A therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune diseases

Cytokine and Growth Factor Reviews

Volumn 30, Issue , 2016, Pages 1-17

  Rutz, Sascha ^a   Eidenschenk, Celine ^a   Kiefer, James R ^a   Ouyang, Wenjun ^b  

^a GENENTECH INC   (United States)

^b AMGEN INC   (United States)

Author keywords

Interleukin 17; Inverse agonist; Nuclear receptor; Posttranslational regulation; Retinoic acid related orphan receptor gamma; Ubiquitinylation

Indexed keywords

INTERLEUKIN 17; LONG UNTRANSLATED RNA; MESSENGER RNA; RETINOID RELATED ORPHAN RECEPTOR ALPHA; RETINOID RELATED ORPHAN RECEPTOR GAMMA; RIBONUCLEASE PROTEIN COMPLEX; UNCLASSIFIED DRUG;

CYTOKINE PRODUCTION; CYTOKINE RESPONSE; ENZYME ACTIVITY; ENZYME REGULATION; GAMMA DELTA T LYMPHOCYTE; HUMAN; IN VIVO STUDY; MULTIPLE SCLEROSIS; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; PRIORITY JOURNAL; PROTEIN ACETYLATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN TARGETING; PSORIASIS; REVIEW; RHEUMATOID ARTHRITIS; TH17 CELL; UBIQUITINATION; ANIMAL; AUTOIMMUNE DISEASE; GENETICS; IMMUNOLOGY; METABOLISM;

ANIMALS; AUTOIMMUNE DISEASES; HUMANS; INTERLEUKIN-17; NUCLEAR RECEPTOR SUBFAMILY 1, GROUP F, MEMBER 3; PROTEIN PROCESSING, POST-TRANSLATIONAL;

EID: 84981747416     PISSN: 13596101     EISSN: 18790305     Source Type: Journal    
DOI: 10.1016/j.cytogfr.2016.07.004     Document Type: Review

References (183)

1. [1] Robinson-Rechavi, M., Escriva Garcia, H., Laudet, V., The nuclear receptor superfamily. J. Cell Sci. 116 (2003), 585–586.
2. [2] Becker-André, M., André, E., DeLamarter, J.F., Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. Biochem. Biophys. Res. Commun. 194 (1993), 1371–1379.
3. [3] Carlberg, C., Hooft van Huijsduijnen, R., Staple, J.K., DeLamarter, J.F., Becker-André, M., RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol. Endocrinol. 8 (1994), 757–770, 10.1210/mend.8.6.7935491.
4. [4] Hirose, T., Smith, R.J., Jetten, A.M., ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem. Biophys. Res. Commun. 205 (1994), 1976–1983, 10.1006/bbrc.1994.2902.
5. [5] Santori, F.R., Nuclear hormone receptors put immunity on sterols. Eur. J. Immunol. 45 (2015), 2730–2741, 10.1002/eji.201545712.
6. [6] Kallen, J.A., Schlaeppi, J.-M., Bitsch, F., Geisse, S., Geiser, M., Delhon, I., et al. X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure 10 (2002), 1697–1707.
7. [7] Stehlin-Gaon, C., Willmann, D., Zeyer, D., Sanglier, S., Van Dorsselaer, A., Renaud, J.-P., et al. All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat. Struct. Biol. 10 (2003), 820–825, 10.1038/nsb979.
8. [8] Wang, Y., Kumar, N., Solt, L.A., Richardson, T.I., Helvering, L.M., Crumbley, C., et al. Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J. Biol. Chem. 285 (2010), 5013–5025, 10.1074/jbc.M109.080614.
9. [9] Wang, Y., Kumar, N., Crumbley, C., Griffin, P.R., Burris, T.P., A second class of nuclear receptors for oxysterols: regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol). Biochim. Biophys. Acta 1801 (2010), 917–923, 10.1016/j.bbalip.2010.02.012.
10. [10] Jin, L., Martynowski, D., Zheng, S., Wada, T., Xie, W., Li, Y., Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol. Endocrinol. 24 (2010), 923–929, 10.1210/me.2009-0507.
11. [11] Hu, X., Wang, Y., Hao, L.-Y., Liu, X., Lesch, C.A., Sanchez, B.M., et al. Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists. Nat. Chem. Biol. 11 (2015), 141–147, 10.1038/nchembio.1714.
12. [12] Santori, F.R., Huang, P., van de Pavert, S.A., Douglass, E.F., Leaver, D.J., Haubrich, B.A., et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab. 21 (2015), 286–297, 10.1016/j.cmet.2015.01.004.
13. [13] Ortiz, M.A., Piedrafita, F.J., Pfahl, M., Maki, R., TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. Mol. Endocrinol. 9 (1995), 1679–1691, 10.1210/mend.9.12.8614404.
14. [14] Ivanov, I.I., McKenzie, B.S., Zhou, L., Tadokoro, C.E., Lepelley, A., Lafaille, J.J., et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126 (2006), 1121–1133, 10.1016/j.cell.2006.07.035.
15. [15] Eberl, G., Littman, D.R., The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches. Immunol. Rev. 195 (2003), 81–90.
16. [16] Jetten, A.M., Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl. Recept Signal., 7, 2009, e003, 10.1621/nrs.07003.
17. [17] Korn, T., Bettelli, E., Oukka, M., Kuchroo, V.K., IL-17 and Th17Cells. Annu. Rev. Immunol. 27 (2009), 485–517, 10.1146/annurev.immunol.021908.132710.
18. [18] Cherrier, M., Ohnmacht, C., Cording, S., Eberl, G., Development and function of intestinal innate lymphoid cells. Curr. Opin. Immunol., 2012, 10.1016/j.coi.2012.03.011.
19. [19] Ghoreschi, K., Laurence, A., Yang, X.-P., Hirahara, K., O'Shea, J.J., T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol. 32 (2011), 395–401, 10.1016/j.it.2011.06.007.
20. [20] Tesmer, L.A., Lundy, S.K., Sarkar, S., Fox, D.A., Th17 cells in human disease. Immunol. Rev. 223 (2008), 87–113, 10.1111/j.1600-065X.2008.00628.x.
21. [21] Chang, M.R., Rosen, H., Griffin, P.R., RORs in autoimmune disease. Curr. Top. Microbiol. Immunol. 378 (2014), 171–182, 10.1007/978-3-319-05879-5_8.
22. [22] Huh, J.R., Littman, D.R., Small molecule inhibitors of RORγt: targeting Th17 cells and other applications. Eur. J. Immunol. 42 (2012), 2232–2237, 10.1002/eji.201242740.
23. [23] Fauber, B.P., Magnuson, S., Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-((ROR (or RORc). J. Med. Chem. 57 (2014), 5871–5892, 10.1021/jm401901d.
24. [24] Isono, F., Fujita-Sato, S., Ito, S., Inhibiting RORγt/Th17 axis for autoimmune disorders. Drug Discov. Today 19 (2014), 1205–1211, 10.1016/j.drudis.2014.04.012.
25. [25] Medvedev, A., Yan, Z.H., Hirose, T., Giguère, V., Jetten, A.M., Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element. Gene 181 (1996), 199–206.
26. [26] He, Y.W., Deftos, M.L., Ojala, E.W., Bevan, M.J., RORgamma t a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity 9 (1998), 797–806.
27. [27] André, E., Gawlas, K., Becker-André, M., A novel isoform of the orphan nuclear receptor RORbeta is specifically expressed in pineal gland and retina. Gene 216 (1998), 277–283.
28. [28] Villey, I., de Chasseval, R., de Villartay, J.P., RORgammaT, a thymus-specific isoform of the orphan nuclear receptor RORgamma/TOR, is up-regulated by signaling through the pre-T cell receptor and binds to the TEA promoter. Eur. J. Immunol. 29 (1999), 4072–4080, 10.1002/(SICI)1521-4141(199912)29:12<4072:AID-IMMU4072>3.0.CO;2-E.
29. [29] Jetten, A.M., Joo, J.H., Retinoid-related orphan receptors (RORs): roles in cellular differentiation and development. Adv. Dev. Biol. 16 (2006), 313–355, 10.1016/S1574-3349(06)16010-X.
30. [30] Jolly, S., Journiac, N., Vernet-der Garabedian, B., Mariani, J., RORalpha, a key to the development and functioning of the brain. Cerebellum 11 (2012), 451–452, 10.1007/s12311-011-0339-1.
31. [31] Fitzsimmons, R.L., Lau, P., Muscat, G.E.O., Retinoid-related orphan receptor alpha and the regulation of lipid homeostasis. J. Steroid Biochem. Mol. Biol. 130 (2012), 159–168, 10.1016/j.jsbmb.2011.06.009.
32. [32] Swaroop, A., Kim, D., Forrest, D., Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat. Rev. Neurosci. 11 (2010), 563–576, 10.1038/nrn2880.
33. [33] Duez, H., Staels, B., The nuclear receptors Rev-erbs and RORs integrate circadian rhythms and metabolism. Diab. Vasc. Dis. Res. 5 (2008), 82–88, 10.3132/dvdr.2008.0014.
34. [34] Kojetin, D.J., Burris, T.P., REV-ERB and ROR nuclear receptors as drug targets. Nat. Rev. Drug Discov. 13 (2014), 197–216, 10.1038/nrd4100.
35. [35] Eberl, G., Marmon, S., Sunshine, M.-J., Rennert, P.D., Choi, Y., Littman, D.R., An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5 (2004), 64–73, 10.1038/ni1022.
36. [36] Eberl, G., Littman, D.R., The role of the nuclear hormone receptor RORγt in the development of lymph nodes and Peyer's patches. Immunol. Rev. 195 (2003), 81–90, 10.1034/j.1600-065X.2003.00074.x.
37. [37] van de Pavert, S.A., Mebius, R.E., New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10 (2010), 664–674, 10.1038/nri2832.
38. [38] Sun, Z., Unutmaz, D., Zou, Y.R., Sunshine, M.J., Pierani, A., Brenner-Morton, S., et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288 (2000), 2369–2373.
39. [39] Kurebayashi, S., Ueda, E., Sakaue, M., Patel, D.D., Medvedev, A., Zhang, F., et al. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl. Acad. Sci. U. S. A. 97 (2000), 10132–10137.
40. [40] Xie, H., Sadim, M.S., Sun, Z., RORgammat recruits steroid receptor coactivators to ensure thymocyte survival. J. Immunol. 175 (2005), 3800–3809.
41. [41] Ueda, E., Kurebayashi, S., Sakaue, M., Backlund, M., Koller, B., Jetten, A.M., High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor RORgamma. Cancer Res. 62 (2002), 901–909.
42. [42] Okada, S., Markle, J.G., Deenick, E.K., Mele, F., Averbuch, D., Lagos, M., et al. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349 (2015), 606–613, 10.1126/science.aaa4282.
43. [43] Ivanov, I.I., Zhou, L., Littman, D.R., Transcriptional regulation of Th17 cell differentiation. Semin. Immunol. 19 (2007), 409–417, 10.1016/j.smim.2007.10.011.
44. [44] Yang, X.O., Pappu, B.P., Nurieva, R., Akimzhanov, A., Kang, H.S., Chung, Y., et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28 (2008), 29–39, 10.1016/j.immuni.2007.11.016.
45. [45] Yang, J., Sundrud, M.S., Skepner, J., Yamagata, T., Targeting Th17 cells in autoimmune diseases. Trends Pharmacol. Sci. 35 (2014), 493–500, 10.1016/j.tips.2014.07.006.
46. [46] Miossec, P., Kolls, J.K., Targeting IL-17 and TH17 cells in chronic inflammation. Nat. Rev. Drug Discov. 11 (2012), 763–776, 10.1038/nrd3794.
47. [47] McEwan, I.J., Nuclear receptors: one big family. Methods Mol. Biol. 505 (2009), 3–18, 10.1007/978-1-60327-575-0_1.
48. [48] Solt, L.A., Griffin, P.R., Burris, T.P., Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics. Curr. Opin. Lipidol. 21 (2010), 204–211, 10.1097/MOL.0b013e328338ca18.
49. [49] Giguère, V., Tini, M., Flock, G., Ong, E., Evans, R.M., Otulakowski, G., Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 8 (1994), 538–553.
50. [50] Giguère, V., Beatty, B., Squire, J., Copeland, N.G., Jenkins, N.A., The orphan nuclear receptor ROR alpha (RORA) maps to a conserved region of homology on human chromosome 15q21-q22 and mouse chromosome 9. Genomics 28 (1995), 596–598, 10.1006/geno.1995.1197.
51. [51] McBroom, L.D., Flock, G., Giguère, V., The nonconserved hinge region and distinct amino-terminal domains of the ROR alpha orphan nuclear receptor isoforms are required for proper DNA bending and ROR alpha-DNA interactions. Mol. Cell. Biol. 15 (1995), 796–808.
52. [52] Sundvold, H., Lien, S., Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem. Biophys. Res. Commun. 287 (2001), 383–390, 10.1006/bbrc.2001.5602.
53. [53] Giguère, V., McBroom, L.D., Flock, G., Determinants of target gene specificity for ROR alpha 1: monomeric DNA binding by an orphan nuclear receptor. Mol. Cell. Biol. 15 (1995), 2517–2526.
54. [54] Schräder, M., Danielsson, C., Wiesenberg, I., Carlberg, C., Identification of natural monomeric response elements of the nuclear receptor RZR/ROR. They also bind COUP-TF homodimers. J. Biol. Chem. 271 (1996), 19732–19736.
55. [55] Kallen, J., Schlaeppi, J.-M., Bitsch, F., Delhon, I., Fournier, B., Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A. J. Biol. Chem. 279 (2004), 14033–14038, 10.1074/jbc.M400302200.
56. [56] Li, Y., Lambert, M.H., Xu, H.E., Activation of nuclear receptors: a perspective from structural genomics. Structure 11 (2003), 741–746.
57. [57] Darimont, B.D., Wagner, R.L., Apriletti, J.W., Stallcup, M.R., Kushner, P.J., Baxter, J.D., et al. Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. 12 (1998), 3343–3356.
58. [58] Glass, C.K., Rosenfeld, M.G., The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14 (2000), 121–141.
59. [59] Heery, D.M., Kalkhoven, E., Hoare, S., Parker, M.G., A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387 (1997), 733–736, 10.1038/42750.
60. [60] McInerney, E.M., Rose, D.W., Flynn, S.E., Westin, S., Mullen, T.M., Krones, A., et al. Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev. 12 (1998), 3357–3368.
61. [61] Heery, D.M., Hoare, S., Hussain, S., Parker, M.G., Sheppard, H., Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors. J. Biol. Chem. 276 (2001), 6695–6702, 10.1074/jbc.M009404200.
62. [62] Nagy, L., Kao, H.Y., Love, J.D., Li, C., Banayo, E., Gooch, J.T., et al. Mechanism of corepressor binding and release from nuclear hormone receptors. Genes Dev. 13 (1999), 3209–3216.
63. [63] Moras, D., Gronemeyer, H., The nuclear receptor ligand-binding domain: structure and function. Curr. Opin. Cell Biol. 10 (1998), 384–391.
64. [64] Nagy, L., Kao, H.Y., Chakravarti, D., Lin, R.J., Hassig, C.A., Ayer, D.E., et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89 (1997), 373–380.
65. [65] Hu, X., Lazar, M.A., The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402 (1999), 93–96, 10.1038/47069.
66. [66] Xu, H.E., Stanley, T.B., Montana, V.G., Lambert, M.H., Shearer, B.G., Cobb, J.E., et al. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature 415 (2002), 813–817, 10.1038/415813a.
67. [67] Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 14 (1995), 3741–3751.
68. [68] Rosenfeld, M.G., Lunyak, V.V., Glass, C.K., Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20 (2006), 1405–1428, 10.1101/gad.1424806.
69. [69] Perissi, V., Rosenfeld, M.G., Controlling nuclear receptors: the circular logic of cofactor cycles. Nat. Rev. Mol. Cell Biol. 6 (2005), 542–554, 10.1038/nrm1682.
70. [70] McKenna, N.J., O'Malley, B.W., Minireview: nuclear receptor coactivators-an update. Endocrinology 143 (2002), 2461–2465, 10.1210/endo.143.7.8892.
71. [71] Xu, W., Nuclear receptor coactivators: the key to unlock chromatin. Biochem. Cell Biol. 83 (2005), 418–428, 10.1139/o05-057.
72. [72] Atkins, G.B., Hu, X., Guenther, M.G., Rachez, C., Freedman, L.P., Lazar, M.A., Coactivators for the orphan nuclear receptor RORalpha. Mol. Endocrinol. 13 (1999), 1550–1557, 10.1210/mend.13.9.0343.
73. [73] Gold, D.A., Baek, S.H., Schork, N.J., Rose, D.W., Larsen, D.D., Sachs, B.D., et al. RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways. Neuron 40 (2003), 1119–1131.
74. [74] Harding, H.P., Atkins, G.B., Jaffe, A.B., Seo, W.J., Lazar, M.A., Transcriptional activation and repression by RORalpha, an orphan nuclear receptor required for cerebellar development. Mol. Endocrinol. 11 (1997), 1737–1746.
75. [75] Harris, J.M., Lau, P., Chen, S.L., Muscat, G.E.O., Characterization of the retinoid orphan-related receptor-alpha coactivator binding interface: a structural basis for ligand-independent transcription. Mol. Endocrinol. 16 (2002), 998–1012, 10.1210/mend.16.5.0837.
76. [76] Kurebayashi, S., Nakajima, T., Kim, S.-C., Chang, C.-Y., McDonnell, D.P., Renaud, J.-P., et al. Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma. Biochem. Biophys. Res. Commun. 315 (2004), 919–927, 10.1016/j.bbrc.2004.01.131.
77. [77] Lau, P., Bailey, P., Dowhan, D.H., Muscat, G.E., Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: rORalpha1 directly interacts with p300 and myoD. Nucleic Acids Res. 27 (1999), 411–420.
78. [78] Johnson, D.R., Lovett, J.M., Hirsch, M., Xia, F., Chen, J.D., NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation. Biochem. Biophys. Res. Commun. 318 (2004), 714–718, 10.1016/j.bbrc.2004.04.087.
79. [79] Jetten, A.M., Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs). Curr. Drug Targets Inflamm. Allergy 3 (2004), 395–412.
80. [80] Littman, D.R., Sun, Z., Unutmaz, D., Sunshine, M.J., Petrie, H.T., Zou, Y.R., Role of the nuclear hormone receptor ROR gamma in transcriptional regulation thymocyte survival, and lymphoid organogenesis. Cold Spring Harb. Symp. Quant. Biol. 64 (1999), 373–381.
81. [81] Greiner, E.F., Kirfel, J., Greschik, H., Huang, D., Becker, P., Kapfhammer, J.P., et al. Differential ligand-dependent protein–protein interactions between nuclear receptors and a neuronal-specific cofactor. Proc. Natl. Acad. Sci. U. S. A. 97 (2000), 7160–7165.
82. [82] Lau, P., Nixon, S.J., Parton, R.G., Muscat, G.E.O., RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. J. Biol. Chem. 279 (2004), 36828–36840, 10.1074/jbc.M404927200.
83. [83] Huh, J.R., Leung, M.W.L., Huang, P., Ryan, D.A., Krout, M.R., Malapaka, R.R.V., et al. Digoxin and its derivatives suppress T(H)17 cell differentiation by antagonizing RORγt activity. Nature, 2011, 10.1038/nature09978.
84. [84] Soroosh, P., Wu, J., Xue, X., Song, J., Sutton, S.W., Sablad, M., et al. Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation. Proc. Natl. Acad. Sci. U. S. A. 111 (2014), 12163–12168, 10.1073/pnas.1322807111.
85. [85] Wang, C., Yosef, N., Gaublomme, J., Wu, C., Lee, Y., Clish, C.B., et al. CD5L/AIM regulates lipid biosynthesis and restrains th17 cell pathogenicity. Cell 163 (2015), 1413–1427, 10.1016/j.cell.2015.10.068.
86. [86] Kurokawa, J., Arai, S., Nakashima, K., Nagano, H., Nishijima, A., Miyata, K., et al. Macrophage-derived AIM is endocytosed into adipocytes and decreases lipid droplets via inhibition of fatty acid synthase activity. Cell Metab. 11 (2010), 479–492, 10.1016/j.cmet.2010.04.013.
87. [87] Gronemeyer, H., Gustafsson, J.-A., Laudet, V., Principles for modulation of the nuclear receptor superfamily. Nat. Rev. Drug Discov. 3 (2004), 950–964, 10.1038/nrd1551.
88. [88] René, O., Fauber, B.P., de, G., Boenig, L., Burton, B., Eidenschenk, C., Everett, C., et al. Minor structural change to tertiary sulfonamide RORc ligands led to opposite mechanisms of action. ACS Med. Chem. Lett. 6 (2015), 276–281, 10.1021/ml500420y.
89. [89] Fauber, B.P., Gobbi, A., Savy, P., Burton, B., Deng, Y., Everett, C., et al. Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists. Bioorg. Med. Chem. Lett. 25 (2015), 4109–4113, 10.1016/j.bmcl.2015.08.028.
90. [90] Fauber, B.P., Gobbi, A., Robarge, K., Zhou, A., Barnard, A., Cao, J., et al. Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists. Bioorg. Med. Chem. Lett. 25 (2015), 2907–2912, 10.1016/j.bmcl.2015.05.055.
91. [91] Solt, L.A., Kumar, N., Nuhant, P., Wang, Y., Lauer, J.L., Liu, J., et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472 (2011), 491–494, 10.1038/nature10075.
92. [92] Scheepstra, M., Leysen, S., van Almen, G.C., Miller, J.R., Piesvaux, J., Kutilek, V., et al. Identification of an allosteric binding site for RORγt inhibition. Nat. Commun., 6, 2015, 8833, 10.1038/ncomms9833.
93. [93] Xiao, S., Yosef, N., Yang, J., Wang, Y., Zhou, L., Zhu, C., et al. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40 (2014), 477–489, 10.1016/j.immuni.2014.04.004.
94. [94] Kumar, N., Lyda, B., Chang, M.R., Lauer, J.L., Solt, L.A., Burris, T.P., et al. Identification of SR 2211: a potent synthetic RORγ-selective modulator. ACS Chem. Biol. 7 (2012), 672–677, 10.1021/cb200496y.
95. [95] Solt, L.A., Kumar, N., He, Y., Kamenecka, T.M., Griffin, P.R., Burris, T.P., Identification of a selective RORγ ligand that suppresses T(H)17 cells and stimulates T regulatory cells. ACS Chem. Biol. 7 (2012), 1515–1519, 10.1021/cb3002649.
96. [96] Huh, J.R., Englund, E.E., Wang, H., Huang, R., Huang, P., Rastinejad, F., et al. Identification of potent and selective diphenylpropanamide RORγ inhibitors. ACS Med. Chem. Lett. 4 (2013), 79–84, 10.1021/ml300286h.
97. [97] Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J. Biol. Chem. 286 (2011), 22707–22710, 10.1074/jbc.C111.250407.
98. [98] Skepner, J., Ramesh, R., Trocha, M., Schmidt, D., Baloglu, E., Lobera, M., et al. Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo. J. Immunol. 192 (2014), 2564–2575, 10.4049/jimmunol.1302190.
99. [99] Chang, M.R., Lyda, B., Kamenecka, T.M., Griffin, P.R., Pharmacologic repression of retinoic acid receptor-related orphan nuclear receptor γ is therapeutic in the collagen-induced arthritis experimental model. Arthritis Rheumatol. 66 (2014), 579–588, 10.1002/art.38272.
100. [100] Wang, Y., Kumar, N., Nuhant, P., Cameron, M.D., Istrate, M.A., Roush, W.R., et al. Identification of SR 1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS Chem. Biol. 5 (2010), 1029–1034, 10.1021/cb100223d.
101. [101] Zhang, W., Zhang, J., Fang, L., Zhou, L., Wang, S., Xiang, Z., et al. Increasing human Th17 differentiation through activation of orphan nuclear receptor retinoid acid-related orphan receptor γ (RORγ) by a class of aryl amide compounds. Mol. Pharmacol. 82 (2012), 583–590, 10.1124/mol.112.078667.
102. [102] Chang, M.R., Dharmarajan, V., Doebelin, C., Garcia-Ordonez, R.D., Novick, S.J., Kuruvilla, D.S., et al. Synthetic RORγt agonists enhance protective immunity. ACS Chem. Biol. 11 (2016), 1012–1018, 10.1021/acschembio.5b00899.
103. [103] West, N.R., McCuaig, S., Franchini, F., Powrie, F., Emerging cytokine networks in colorectal cancer. Nat. Rev. Immunol. 15 (2015), 615–629, 10.1038/nri3896.
104. [104] Zou, W., Restifo, N.P., T(H)17 cells in tumour immunity and immunotherapy. Nat. Rev. Immunol. 10 (2010), 248–256, 10.1038/nri2742.
105. [105] Anbalagan, M., Huderson, B., Murphy, L., Rowan, B.G., Post-translational modifications of nuclear receptors and human disease. Nucl. Recept Signal., 10, 2012, e001, 10.1621/nrs.10001.
106. [106] Faus, H., Haendler, B., Post-translational modifications of steroid receptors. Biomed. Pharmacother. 60 (2006), 520–528, 10.1016/j.biopha.2006.07.082.
107. [107] Rochette-Egly, C., Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell. Signal. 15 (2003), 355–366.
108. [108] Lim, H.W., Kang, S.G., Ryu, J.K., Schilling, B., Fei, M., Lee, I.S., et al. SIRT1 deacetylates RORγt and enhances Th17 cell generation. J. Exp. Med. 212 (2015), 607–617, 10.1084/jem.20132378.
109. [109] Wu, Q., Nie, J., Gao, Y., Xu, P., Sun, Q., Yang, J., et al. Reciprocal regulation of RORγt acetylation and function by p300 and HDAC1. Sci. Rep., 5, 2015, 16355, 10.1038/srep16355.
110. [110] Gu, W., Roeder, R.G., Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90 (1997), 595–606.
111. [111] Hoberg, J.E., Popko, A.E., Ramsey, C.S., Mayo, M.W., IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol. Cell. Biol. 26 (2006), 457–471, 10.1128/MCB.26.2.457-471.2006.
112. [112] Ghosh, A.K., Varga, J., The transcriptional coactivator and acetyltransferase p300 in fibroblast biology and fibrosis. J. Cell Physiol. 213 (2007), 663–671, 10.1002/jcp.21162.
113. [113] Kwon, H.-S., Ott, M., The ups and downs of SIRT1. Trends Biochem. Sci. 33 (2008), 517–525, 10.1016/j.tibs.2008.08.001.
114. [114] Zhang, J., Lee, S.-M., Shannon, S., Gao, B., Chen, W., Chen, A., et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J. Clin. Invest. 119 (2009), 3048–3058, 10.1172/JCI38902.
115. [115] Zhang, R., Chen, H.-Z., Liu, J.-J., Jia, Y.-Y., Zhang, Z.-Q., Yang, R.-F., et al. SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J. Biol. Chem. 285 (2010), 7097–7110, 10.1074/jbc.M109.038604.
116. [116] Beier, U.H., Akimova, T., Liu, Y., Wang, L., Hancock, W.W., Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells. Curr. Opin. Immunol. 23 (2011), 670–678, 10.1016/j.coi.2011.07.002.
117. [117] Kwon, H.-S., Lim, H.W., Wu, J., Schnölzer, M., Verdin, E., Ott, M., Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J. Immunol. 188 (2012), 2712–2721, 10.4049/jimmunol.1100903.
118. [118] Weissman, A.M., Themes and variations on ubiquitylation. Nat. Rev. Mol. Cell Biol. 2 (2001), 169–178, 10.1038/35056563.
119. [119] Kulathu, Y., Komander, D., Atypical ubiquitylation – the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat. Rev. Mol. Cell Biol. 13 (2012), 508–523, 10.1038/nrm3394.
120. [120] Rutz, S., Kayagaki, N., Phung, Q.T., Eidenschenk, C., Noubade, R., Wang, X., et al. Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells. Nature, 2014, 10.1038/nature13979.
121. [121] Kathania, M., Khare, P., Zeng, M., Cantarel, B., Zhang, H., Ueno, H., et al. Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination. Nat. Immunol., 2016, 10.1038/ni.3488.
122. [122] Wang, X., Yang, J., Han, L., Zhao, K., Wu, Q., Bao, L., et al. TRAF5-mediated K63-linked polyubiquitination play essential role in positive regulation of RORγt on promoting IL-17A expression. J. Biol. Chem., 2015, 10.1074/jbc.M115.664573 (jbc.M115.664573).
123. [123] Xie, P., TRAF molecules in cell signaling and in human diseases. J Mol Signal, 8, 2013, 7, 10.1186/1750-2187-8-7.
124. [124] Liu, X., Li, H., Zhong, B., Blonska, M., Gorjestani, S., Yan, M., et al. USP18 inhibits NF-γB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. J. Exp. Med. 210 (2013), 1575–1590, 10.1084/jem.20122327.
125. [125] Zhong, B., Liu, X., Wang, X., Chang, S.H., Liu, X., Wang, A., et al. Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25. Nature, 2012, 10.1038/ni.2427.
126. [126] Han, L., Yang, J., Wang, X., Wu, Q., Yin, S., Li, Z., et al. The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells. J. Biol. Chem. 289 (2014), 25546–25555, 10.1074/jbc.M114.565291.
127. [127] Yang, J., Xu, P., Han, L., Guo, Z., Wang, X., Chen, Z., et al. Cutting edge: ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt. J. Immunol. 194 (2015), 4094–4097, 10.4049/jimmunol.1401451.
128. [128] Zhang, L., Zhou, F., Drabsch, Y., Gao, R., Snaar-Jagalska, B.E., Mickanin, C., et al. USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor. Nat. Cell Biol. 14 (2012), 717–726, 10.1038/ncb2522.
129. [129] Vucic, D., Dixit, V.M., Wertz, I.E., Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat. Rev. Mol. Cell Biol. 12 (2011), 439–452, 10.1038/nrm3143.
130. [130] Keppler, B.R., Archer, T.K., Kinyamu, H.K., Emerging roles of the 26 S proteasome in nuclear hormone receptor-regulated transcription. Biochim. Biophys. Acta 1809 (2011), 109–118, 10.1016/j.bbagrm.2010.08.005.
131. [131] Zhou, W., Slingerland, J.M., Links between oestrogen receptor activation and proteolysis: relevance to hormone-regulated cancer therapy. Nat. Rev. Cancer. 14 (2014), 26–38.
132. [132] Lee, J.H., Lee, M.J., Emerging roles of the ubiquitin-proteasome system in the steroid receptor signaling. Arch. Pharm. Res. 35 (2012), 397–407, 10.1007/s12272-012-0301-x.
133. [133] Jetten, A.M., Joo, J.H., Retinoid-related orphan receptors (RORs): roles in cellular differentiation and development. Adv. Dev. Biol. 16 (2006), 313–355, 10.1016/S1574-3349(06)16010-X.
134. [134] Lonard, D.M., Nawaz, Z., Smith, C.L., O'Malley, B.W., The 26 S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. Mol. Cell 5 (2000), 939–948.
135. [135] Moraitis, A.N., Giguère, V., The co-repressor hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation. J. Biol. Chem. 278 (2003), 52511–52518, 10.1074/jbc.M308152200.
136. [136] Moraitis, A.N., Giguère, V., Thompson, C.C., Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol. Cell. Biol. 22 (2002), 6831–6841, 10.1128/MCB.22.19.6831-6841.2002.
137. [137] Straus, D.S., Glass, C.K., Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 28 (2007), 551–558, 10.1016/j.it.2007.09.003.
138. [138] Klemann, C., Raveney, B.J.E., Klemann, A.K., Ozawa, T., von Hörsten, S., Shudo, K., et al. Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis. Am. J. Pathol. 174 (2009), 2234–2245, 10.2353/ajpath.2009.081084.
139. [139] Mayne, C.G., Spanier, J.A., Relland, L.M., Williams, C.B., Hayes, C.E., 1,25-Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis. Eur. J. Immunol. 41 (2011), 822–832, 10.1002/eji.201040632.
140. [140] Wen, H., Baker, J.F., Vitamin D, immunoregulation, and rheumatoid arthritis. J. Clin. Rheumatol. 17 (2011), 102–107, 10.1097/RHU.0b013e31820edd18.
141. [141] Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317 (2007), 256–260, 10.1126/science.1145697.
142. [142] Elias, K.M., Laurence, A., Davidson, T.S., Stephens, G., Kanno, Y., Shevach, E.M., et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111 (2008), 1013–1020, 10.1182/blood-2007-06-096438.
143. [143] Gampe, R.T., Montana, V.G., Lambert, M.H., Miller, A.B., Bledsoe, R.K., Milburn, M.V., et al. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol. Cell 5 (2000), 545–555.
144. [144] Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med. 206 (2009), 2079–2089, 10.1084/jem.20082771.
145. [145] Dumas, B., Harding, H.P., Choi, H.S., Lehmann, K.A., Chung, M., Lazar, M.A., et al. A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-Erb. Mol. Endocrinol. 8 (1994), 996–1005, 10.1210/mend.8.8.7997240.
146. [146] Yin, L., Lazar, M.A., The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol. Endocrinol. 19 (2005), 1452–1459, 10.1210/me.2005-0057.
147. [147] Raghuram, S., Stayrook, K.R., Huang, P., Rogers, P.M., Nosie, A.K., McClure, D.B., et al. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nat. Struct. Mol. Biol. 14 (2007), 1207–1213, 10.1038/nsmb1344.
148. [148] Yu, X., Rollins, D., Ruhn, K.A., Stubblefield, J.J., Green, C.B., Kashiwada, M., et al. TH17 cell differentiation is regulated by the circadian clock. Science 342 (2013), 727–730, 10.1126/science.1243884.
149. [149] Farez, M.F., Mascanfroni, I.D., Méndez-Huergo, S.P., Yeste, A., Murugaiyan, G., Garo, L.P., et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162 (2015), 1338–1352, 10.1016/j.cell.2015.08.025.
150. [150] Ciofani, M., Madar, A., Galan, C., Sellars, M., Mace, K., Pauli, F., et al. A validated regulatory network for th17 cell specification. Cell 151 (2012), 289–303, 10.1016/j.cell.2012.09.016.
151. [151] Okamoto, K., Iwai, Y., Oh-Hora, M., Yamamoto, M., Morio, T., Aoki, K., et al. IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors. Nature 464 (2010), 1381–1385, 10.1038/nature08922.
152. [152] Zhang, F., Meng, G., Strober, W., Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat. Immunol. 9 (2008), 1297–1306, 10.1038/ni.1663.
153. [153] Dang, E.V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., et al. Control of TH17/Treg balance by hypoxia-Inducible factor 1. Cell, 2011, 10.1016/j.cell.2011.07.033.
154. [154] Jain, R., Chen, Y., Kanno, Y., Joyce-Shaikh, B., Vahedi, G., Hirahara, K., et al. Interleukin-23-Induced transcription factor blimp-1 promotes pathogenicity of t helper 17Cells. Immunity 44 (2016), 131–142, 10.1016/j.immuni.2015.11.009.
155. [155] Zhou, L., Ivanov, I.I., Spolski, R., Min, R., Shenderov, K., Egawa, T., et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8 (2007), 967–974, 10.1038/ni1488.
156. [156] Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441 (2006), 235–238, 10.1038/nature04753.
157. [157] Ghoreschi, K., Laurence, A., Yang, X.-P., Tato, C.M., McGeachy, M.J., Konkel, J.E., et al. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature 467 (2010), 967–971, 10.1038/nature09447.
158. [158] Zheng, Y., Danilenko, D., Valdez, P., Kasman, I., Eastham-Anderson, J., Wu, J., et al. Interleukin-22 a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445 (2007), 648–651.
159. [159] Rutz, S., Noubade, R., Eidenschenk, C., Ota, N., Zeng, W., Zheng, Y., et al. Transcription factor c-Maf mediates the TGF-β-dependent suppression of IL-22 production in T(H)17 cells. Nat. Immunol. 12 (2011), 1238–1245, 10.1038/ni.2134.
160. [160] Zhou, L., Lopes, J.E., Chong, M.M.W., Ivanov, I.I., Min, R., Victora, G.D., et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453 (2008), 236–240, 10.1038/nature06878.
161. [161] Ichiyama, K., Yoshida, H., Wakabayashi, Y., Chinen, T., Saeki, K., Nakaya, M., et al. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J. Biol. Chem. 283 (2008), 17003–17008, 10.1074/jbc.M801286200.
162. [162] Du, J., Huang, C., Zhou, B., Ziegler, S.F., Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J. Immunol. 180 (2008), 4785–4792.
163. [163] Sefik, E., Geva-Zatorsky, N., Oh, S., Konnikova, L., Zemmour, D., McGuire, A.M., et al. Individual intestinal symbionts induce a distinct population of RORγ + regulatory T cells. Science, 2015, 10.1126/science.aaa9420 (aaa9420).
164. [164] Ohnmacht, C., Park, J.-H., Cording, S., Wing, J.B., Atarashi, K., Obata, Y., et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science, 2015, 10.1126/science.aac4263 (aac4263).
165. [165] Yang, B.-H., Hagemann, S., Mamareli, P., Lauer, U., Hoffmann, U., Beckstette, M., et al. Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunology., 2015, 10.1038/mi.2015.74.
166. [166] Maeda, N., Kasukawa, T., Oyama, R., Gough, J., Frith, M., Engström, P.G., et al. Transcript annotation in FANTOM3: mouse gene catalog based on physical cDNAs. PLoS Genet., 2, 2006, e62, 10.1371/journal.pgen.0020062.
167. [167] Djebali, S., Davis, C.A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., et al. Landscape of transcription in human cells. Nature 489 (2012), 101–108, 10.1038/nature11233.
168. [168] Mercer, T.R., Dinger, M.E., Mattick, J.S., Long non-coding RNAs: insights into functions. Nat. Rev. Genet. 10 (2009), 155–159, 10.1038/nrg2521.
169. [169] Fatica, A., Bozzoni, I., Long non-coding RNAs: new players in cell differentiation and development. Nat. Rev. Genet. 15 (2014), 7–21, 10.1038/nrg3606.
170. [170] Kung, J.T.Y., Colognori, D., Lee, J.T., Long noncoding RNAs: past, present, and future. Genetics 193 (2013), 651–669, 10.1534/genetics.112.146704.
171. [171] Rinn, J.L., Chang, H.Y., Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81 (2012), 145–166, 10.1146/annurev-biochem-051410-092902.
172. [172] Hu, G., Tang, Q., Sharma, S., Yu, F., Escobar, T.M., Muljo, S.A., et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat. Immunol. 14 (2013), 1190–1198, 10.1038/ni.2712.
173. [173] Spurlock, C.F., Tossberg, J.T., Guo, Y., Collier, S.P., Crooke, P.S., Aune, T.M., Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nat. Commun., 6, 2015, 6932, 10.1038/ncomms7932.
174. [174] Huang, W., Thomas, B., Flynn, R.A., Gavzy, S.J., Wu, L., Kim, S.V., et al. DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature 528 (2015), 517–522, 10.1038/nature16193.
175. [175] Linder, P., Jankowsky, E., From unwinding to clamping – the DEAD box RNA helicase family. Nat. Rev. Mol. Cell Biol. 12 (2011), 505–516, 10.1038/nrm3154.
176. [176] Clark, E.L., Coulson, A., Dalgliesh, C., Rajan, P., Nicol, S.M., Fleming, S., et al. The RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer. Cancer Res. 68 (2008), 7938–7946, 10.1158/0008-5472.CAN-08-0932.
177. [177] Wortham, N.C., Ahamed, E., Nicol, S.M., Thomas, R.S., Periyasamy, M., Jiang, J., et al. The DEAD-box protein p72 regulates ERalpha-/oestrogen-dependent transcription and cell growth, and is associated with improved survival in ERalpha-positive breast cancer. Oncogene 28 (2009), 4053–4064, 10.1038/onc.2009.261.
178. [178] Hsieh, C.L., Donlon, T.A., Darras, B.T., Chang, D.D., Topper, J.N., Clayton, D.A., et al. The gene for the RNA component of the mitochondrial RNA-processing endoribonuclease is located on human chromosome 9p and on mouse chromosome 4. Genomics 6 (1990), 540–544.
179. [179] Martin, A.N., Li, Y., RNase MRP RNA and human genetic diseases. Cell Res. 17 (2007), 219–226, 10.1038/sj.cr.7310120.
180. [180] Huang, W., Littman, D.R., Regulation of RORγt in inflammatory lymphoid cell differentiation. Cold Spring Harb. Symp. Quant. Biol., 027615, 2016, 10.1101/sqb.2015.80.027615.
181. [181] Chao, J., Enyedy, I., Van Vloten, K., Marcotte, D., Guertin, K., Hutchings, R., et al. Discovery of biaryl carboxylamides as potent RORγ inverse agonists. Bioorg. Med. Chem. Lett. 25 (2015), 2991–2997, 10.1016/j.bmcl.2015.05.026.
182. [182] Fauber, B.P., René, O., Deng, Y., Devoss, J., Eidenschenk, C., Everett, C., et al. Discovery of 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORγ) inverse agonist. J. Med. Chem. 58 (2015), 5308–5322, 10.1021/acs.jmedchem.5b00597.
183. [183] Kumar, N., Solt, L.A., Conkright, J.J., Wang, Y., Istrate, M.A., Busby, S.A., et al. The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist. Mol. Pharmacol. 77 (2010), 228–236, 10.1124/mol.109.060905.