DGCR14 Induces Il17a Gene Expression through the RORγ/BAZ1B/RSKS2 Complex

Abstract

The Dgcr14/Es2 gene is located in a chromosomal region the loss of which has been associated with DiGeorge syndrome, a cause of immunodeficiency, heart defects, and skeletal abnormalities. However, the role of DGCR14 protein remains to be elucidated. Here, I found that DGCR14 protein acts as a coactivator of ROR␥t in T H 17 cells. Biochemical purification of the ROR␥ coregulator complex allowed me to identify the associated DGCR14 protein by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Overexpression of Dgcr14 mRNA enhanced ROR␥t-mediated transcriptional activity and facilitated T H 17 cell differentiation. Furthermore, knockdown of Dgcr14 reduced Il17a mRNA expression. I also found that DGCR14 associated with ribosomal S6 kinase 2 (RSK2, also called RpS6ka3) and BAZ1B, both of which were recruited to the Il17a promoter during T H 17 cell differentiation. Knockdown of Baz1b or RpS6ka3 also reduced Il17a mRNA expression, and Baz1b knockdown increased transcriptional suppressive histone marks (histone H3K9me3) on the Il17a promoter. My findings showed the roles of DGCR14, RSK2, and BAZ1B in the transcriptional regulation of Il17a mRNA during T H 17 cell differentiation. Retinoid-related orphan nuclear receptor gamma (ROR␥, also called Rorc or Nr1f3) is a member of the nuclear hormone receptor (NR) superfamily. ROR␥ regulates gene transcription by binding as a monomer to specific ROR response elements (ROREs) consisting of the consensus core motif RGGTCA preceded by a 6-bp A/T-rich sequence (1). ROR␥ controls circadian rhythm, lymphocyte development, and lipid and glucose homeostasis. ROR␥ expression exhibits an oscillatory pattern (low levels during the day and maximal levels at night) in the liver, brown adipose tissue, and kidneys (2). Mice deficient in ROR␥ exhibit improved insulin sensitivity and glucose tolerance because of reduced hepatic gluconeogenesis, particularly during the daytime (3).More importantly, ROR␥ knockout mice lack peripheral and mesenteric lymph nodes and Peyer's patches (4). Furthermore, ROR␥t, which is an isoform encoded by the Rorc gene, is highly expressed in lymphocytes and acts as a key regulator in the development of T H 17 cells (5). The N-terminal region amino acid sequence of ROR␥t differs from that of ROR␥, but the DNA-and ligand-binding regions are conserved. ROR␥t knockout mice have diminished numbers of T H 17 cells and are protected against experimental autoimmune encephalomyelitis (2). Because T H 17 cells play a pivotal role in autoimmune diseases, suppression of the transcriptional activities of ROR␥t is critical for developing therapeutics for T H 17-mediated autoimmune disorders, including multiple sclerosis and rheumatoid arthritis. Recent studies have described the synthesis of inverse agonists of ROR␥ to abrogate T H 17 cell function (6-9). However, the molecular mechanism of ROR␥-dependent transcriptional regulation is not fully understood.In general, transcriptional control by NRs depends on multiprotein coregulatory complexes (10, 1...

In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?

“…A recent large-scale protein interactome study identified DGCR14 as a non-core component of the spliceosome C complex, suggesting a role in mRNA processing [191–193]. Indeed, Dgcr14 apparently regulates IL17a transcription during TH17 cell differentiation in vitro [194], perhaps relevant for immune dysfunction in 22q11DS. In human, DGCR14 is expressed in the heart, brain, and skeletal muscle [195].…”

Transcriptional coregulator Ess2 controls survival of post-thymic CD4+ T cells through the Myc and IL-7 signaling pathways

“…We recently identified Ess2 (also known as Dgcr14 or Es2) as a transcriptional coregulator of retinoid-related orphan nuclear receptor gamma/gamma-t (RORt) through biochemical purification and matrix-assisted laser desorption ionization-time of flight mass spectrometry analysis (2).…”

“…While genetically modified mouse models expressing 22q11DS phenotypes have been reported, immunodeficiency-related genes within 22q11. 2 have not yet been identified.…”

Λειτουργική Ανάλυση Του Γονιδίου FRA10AC1 Του Ανθρώπου Στο Πλαίσιο Του Δικτύου Πρωτεϊνικών Αλληλεπιδράσεων Του Σωματίου Συναρμογής

“…Όπως αναφέρθηκε και προηγουμένως, η DGCR14 εντοπίζεται στο πυρηνόπλασμα (Sarafidou et al υπό συγγραφή, http://www.proteinatlas.org/) και ορθόλογα μόριά της έχουν ταυτοποιηθεί αποκλειστικά σε ευκαρυωτικούς. Πρόσφατες μελέτες υποδεικνύουν τη συμμετοχή της DGCR14 στη ρύθμιση της έκφρασης της ιντερλευκίνης 17α στα προ-φλεγμονώδη Τβοηθητικά λεμφοκύτταρα (ΤH17-λεμφοκύτταρα) (Takada 2015) και στη διαδικασία της συναρμογής (Noma et al 2014, Dutcher et al 2018.…”

“…Ειδικότερα στην ερευνητική εργασία του Takada (2015) έχει δειχθεί ότι η πρωτεΐνη DGCR14 λειτουργεί ως ρυθμιστής ενός μέλους της οικογένειας των πυρηνικών υποδοχέων (υποδοχέας RORγ) οι οποίοι δρουν ως μεταγραφικοί παράγοντες. Ο υποδοχέας αυτός ελέγχει την μεταγραφή γονιδίων που ρυθμίζουν τον κιρκαδικό ρυθμό, την ομοιόσταση των λιπιδίων και της γλυκόζης (Jetten et al 2007) και έχει προταθεί ότι είναι βασικός ρυθμιστής της διαφοροποίησης των ΤH17-λεμφοκυττάρων (Ivanov et al 2006).…”