title: Post-translational regulation of RORγt-A therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune diseases.
abstract: Retinoic acid-related orphan receptor gamma t (RORγt) is a nuclear receptor, which is selectively expressed by various lymphocytes. RORγt is critical for the development of secondary and tertiary lymphoid organs, and for the thymic development of the T cell lineage. RORγt has been extensively studied as the master transcription factor of IL-17 expression and Th17 cells, which are strongly associated with various inflammatory and autoimmune conditions. Given its essential role in promoting pro-inflammatory responses, it is not surprising that the expression of RORγt is tightly controlled. By its nature as a nuclear receptor, RORγt activity is also regulated in a ligand-dependent manner, which makes it an attractive drug target. In addition, multiple post-translational mechanisms, including post-translational modifications, such as acetylation and ubiquitinylation, as well as interactions with various co-factors, modulate RORγt function. Here we attempt a comprehensive review of the post-translational regulation of RORγt, an area that holds the potential to transform the way we target the RORγt/IL-17 pathway, by enabling the development of safe and highly selective modulators of RORγt activity.
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. Electronic address: saschar@gene.com.
authors.forename: Sascha
authors.initials: S
authors.lastname: Rutz
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: Department of Structural Biology, Genentech, South San Francisco, CA, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.affiliation: Department of Inflammation and Oncology, Amgen, South San Francisco, CA, USA. Electronic address: wouyang@amgen.com.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
keywords: Interleukin-17; Inverse agonist; Nuclear receptor; Posttranslational regulation; Retinoic acid-related orphan receptor gamma; Ubiquitinylation