Retinoids induce Nur77-dependent apoptosis in mouse thymocytes

• Published in: Biochimica et biophysica acta Vol. 1853; no. 3; pp. 660 - 670
• Main Authors: Kiss, Beáta, Tóth, Katalin, Sarang, Zsolt, Garabuczi, Éva, Szondy, Zsuzsa
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2015
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cell Death - drug effects; Cell Death - genetics; Cells, Cultured; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; Gene Expression Regulation - drug effects; Mice; Mice, Knockout; Mitochondria - drug effects; Mitochondria - physiology; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - physiology; Nur77; Retinoid; Retinoids - pharmacology; Thymocyte; Thymocytes - drug effects; Thymocytes - physiology; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; Up-Regulation - drug effects; Up-Regulation - genetics; Bcl-2; 9cRA; RAR; RALDH; STAT1; Thymocyte; Retinoid; Nur77; DP; RXR; FasL; ATRA; Bid; NDG-1; Apoptosis
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2014.12.035

Nur77 is a transcription factor, which plays a determinant role in mediating T cell receptor-induced cell death of thymocytes. In addition to regulation of transcription, Nur77 contributes to apoptosis induction by targeting mitochondria, where it can convert Bcl-2, an anti-apoptotic protein into a proapoptotic molecule. Previous studies have demonstrated that retinoids are actively produced in the mouse thymus and can induce a transcription-dependent apoptosis in mouse thymocytes. Here we show that retinoic acids induce the expression of Nur77, and retinoid-induced apoptosis is completely dependent on Nur77, as retinoids were unable to induce apoptosis in Nur77 null thymocytes. In wild-type thymocytes retinoids induced enhanced expression of the apoptosis-related genes FasL, TRAIL, NDG-1, Gpr65 and Bid, all of them in a Nur77-dependent manner. The combined action of these proteins led to Caspase 8-dependent Bid cleavage in the mitochondria. In addition, we could demonstrate the Nur77-dependent induction of STAT1 leading to enhanced Bim expression, and the mitochondrial translocation of Nur77 leading to the exposure of the Bcl-2/BH3 domain. The retinoid-induced apoptosis was dependent on both Caspase 8 and STAT1. Our data together indicate that retinoids induce a Nur77-dependent cell death program in thymocytes activating the mitochondrial pathway of apoptosis. •Retinoids induce the expression of the Nur77 transcription factor.•Nur77 induces the expression of Bid, FasL, TRAIL, NDG-1, STAT1 and transglutaminase 2.•FasL, TRAIL and NDG-1 leads to Caspase-8 activation and Bid cleavage.•STAT1 upregulates Bim.•tBid, Bim, Nur77 and transglutaminase 2 acting in the mitochondria initiate apoptosis.