Perez-Sieira, S.; Martinez, G.; Porteiro, B.; Lopez, M.; Vidal, A.; Nogueiras, R.; Dieguez, C. Female Nur77-deficient mice show increased susceptibility to diet-induced obesity. Kim, Y.C. The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. Nr4a transcription is also rapidly induced in CD4+ T cells following engagement of the TCR by Ag. Early precursors and molecular determinants of tissue-resident memory CD8+ T lymphocytes revealed by single-cell RNA sequencing. These data support the ongoing studies to understand mechanisms by which the Nr4a’s induce or inhibit proliferation as potential therapeutic intervention for various conditions. Zhu, W.; Cowie, A.; Wasfy, G.W. Raveney BJE, Oki S, Yamamura T. Nuclear Receptor NR4A2 Orchestrates Th17 Cell-Mediated Autoimmune Inflammation via IL-21 Signalling. It is thus unlikely that the effects observed in TKO mice generated with the Foxp3-Cre system are solely the consequence of poorly matured Foxp3+ thymocytes (74). ; et al. Mol Cell Biol (1997) 17:5946–51. ; Choi, J.; Ahn, K.J. When subjected to partial hepatectomy Nr4a1 deficient mice generated by homologous recombination showed increase in NF-κB and STAT3 protein levels which in turn induced Cyclin B1, Cyclin D1, Cyclin E1, Cdk4 and Cdk2 expression within 24 h, demonstrating that Nr4a1 limits regeneration in hepatocytes [, While Nr4a1 and Nr4a2 inhibit proliferation in liver tissues, Nr4a3 promotes proliferation in both hepatocytes and hepatic stellate cells. Immunity (2018) 48:327–338.e5. We show that NR4A3-deficient murine CD8 + T cells differentiate preferentially into memory precursor and central memory cells, but also produce more cytokines. Therefore, only thymocytes expressing a useful TCR (eventually able to recognize a foreign Ag in association with self-MHC molecules) will survive (positive selection) during differentiation while those expressing an auto-reactive TCR will be physically or functionally eliminated from the repertoire (negative selection). ; van Tiel, C.M. ; Goode, J.M. In an intestinal ischemia mouse model, the mice treated with the Nr4a2 activator C-DIM12 presented increased Ki67+ cells and better recovery [, Knockdown of Nr4a1 and Nr4a2 by in mesenchymal stromal cells increased cell cycle progression and overexpression impeded proliferation by inducing a G1 cell cycle block [, Neural tissue presented mixed results with regards to Nr4a2 and proliferation. As β-cell loss and dysfunction are key aspects of diabetes pathology, β-cell proliferation would enable islet transplants and restored insulin secretion. doi: 10.1038/367277a0, 14. Furthermore, Nr4a1 mutants blocked the VEGF-A mediated proliferation effect. ; Harding, A.; Stark, A.; Cooney, G.J. Front. The functional importance of NR4As in CD8+ T cell exhaustion during cancer was recently described (67, 88). Legname G, Seddon B, Lovatt M, Tomlinson P, Sarner N, Tolaini M, et al. J Exp Med (2005) 202:111–21. ; Kim, Y.S. ; Kim, K.; Singh, M.; Safe, S. The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Int Immunopharmacol (2015) 28:841–5. Goldar, S.; Khaniani, M.S. without analyzing cells individually deficient for Nr4a1, Nr4a2, and Nr4a3, and their DKOs. Myers, S.A.; Eriksson, N.; Burow, R.; Wang, S.C.; Muscat, G.E. doi: 10.1073/pnas.1309378110, 111. ; Muscat, G.E. Previous work on tissue microarrays suggests that NR4A3 immunohistochemistry (IHC) may be useful in the diagnosis of AciCC. Finally, this section will focus on the role of the NR4A family in αβ-thymocyte selection, since to our knowledge the NR4As have not been reported to regulate the development of any other thymic lineages. However, it is unclear whether this increased autoimmunity is due to changes in thymocyte development or peripheral T cell function. ; Zhang, X.k. ; Otermin Rubio, I.; de Waard, V.; de Vries, C.J.M. Pols, T.W. Cutting Edge: The Orphan Nuclear Receptor Nr4a1 Regulates CD8+ T Cell Expansion and Effector Function through Direct Repression of Irf4. Xue L, Chiang L, Kang C, Winoto A. The authors demonstrated that pharmacological inhibition of ERRα or shRNA knockdown of Esrra partially reversed the phenotype (cytokine production and metabolism) of NR4A1-deficient CD4+ T cells and reduced EAE disease severity of Nr4a1−/− mice (69). Qin, D.D. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. ; Zhao, W.X. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. The insulin sensitizing drugs pioglitazone and troglitazone increase adipose tissue glucose uptake and increase expression of Nr4a1 and Nr4a3 [, Loss of Nr4a1 or Nr4a3 but not Nr4a2, in the 832/13 INS-1 β-cell line decreased expression of the glycolytic gene Eno1 [, Changes in fuel metabolism are essential for immune cell differentiation and clonal expansion. In melanoma, Nr4a1 translocates to the mitochondria and stabilize TPβ of the mitochondrial trifunctional protein through direct binding. This NFAT construct induces an exhausted/dysfunctional transcriptional program in CD8+ T cells (96). During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. ; Eriksson, N.A. Among the activation-induced genes are all the Nr4a transcription factors which are rapidly and transiently induced at the early effector stage. EMBO J (2003) 22:6526–36. The statements, opinions and data contained in the journal, © 1996-2021 MDPI (Basel, Switzerland) unless otherwise stated. Yu, C.; Cui, S.; Zong, C.; Gao, W.; Xu, T.; Gao, P.; Chen, J.; Qin, D.; Guan, Q.; Liu, Y.; et al. ; Kim, J.-Y. Finally, it was reported that NR4A1 expression is also an accurate and specific marker to identify human T cells that have recently been activated via their TCRs thus validating the use of Nr4a1 induction as specific marker of recent TCR signaling (90). Transcriptomic analysis reveals that better tumor control by NR4A triple-deficient CD8+ T cells is associated with the induction of the effector T cells gene signature while those for exhausted and memory T cells were down-regulated (67). Zhou, H.; Du, W.; Li, Y.; Shi, C.; Hu, N.; Ma, S.; Wang, W.; Ren, J. Adhikari, P.; Orozco, D.; Randhawa, H.; Wolf, F.W. The Nr4a’s play a role in liver, muscle and adipose tissue controlling the production and usage of lipids. A more recent study using adoptive transfer of Nr4a1−/− TCR transgenic CD8+ T cells followed by acute LCMV infection showed that NR4A1 deficiency increased CD8+ T cell expansion and function but did not affect MPEC/SLEC differentiation, although T-bet expression, a transcription factor important for SLEC generation, was increased (88). What we can conclude is that their regulatory network is complicated and more research needs to be done fully illuminate their function in regulating apoptotic pathways and future use for therapeutic treatments. The deletion of Nr4a1 in the 2D2 TCR transgenic mouse model of EAE led to accelerated and more severe disease with an increase in IFN-γ and IL-17 secreting CD4+ T cells within the central nervous system. showed that combined deficiency in NR4A1 and Bim, a key inducer of thymocyte apoptosis (54), did not further impair clonal deletion compared to NR4A1-deficiency alone. While none of these targets were shown to be required for the thymocyte apoptosis induced by a full-length NR4A1 transgene, we caution that thymic phenotypes in NR4A transgenic mice may not accurately represent endogenous NR4A function during thymocyte selection since NR4A transgenes were active during the DN stage (e.g., Lck proximal promoter), not the DP stage where negative selection first occurs (15, 39, 42, 43). A follow-up study by the same group, showed Nr4a2 transcription was selectively higher in IL-17- or IL-17/IFN-γ-producing CD4+ T cells when compared to IFN-γ-producing CD4+ T cells during EAE and experimental autoimmune uveitis (EAU) (115). Upon receipt of a high affinity TCR signal, self-reactive thymocytes undergo negative selection which includes apoptosis induction (clonal deletion) or functional inactivation (anergy). Dequiedt F, Van Lint J, Lecomte E, Van Duppen V, Seufferlein T, Vandenheede JR, et al. beta-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion. ; DeMayo, F.J.; O’Malley, B.W. ; Stebbins, J.; Reed, J.C.; Dawson, M.I. Unfortunately, cytokine production or the generation of CD8+ T cell memory were not evaluated in this setting. doi: 10.1038/ni.2710, 110. Conversely, its suppression decreased IFN-γ and IL-17 production and the induction of EAE was reduced following the adoptive transfer of encephalitogenic CD4+ T cells in which NR4A2 expression was reduced using siRNA when compared to control CD4+ T cells (114). J Clin Invest (2016) 126:3905–16. Koenis, D.S. This was tested in vivo using an oral tolerance model where Nr4a1 deletion increased IL-2 and IFN-γ production and prevented the establishment of CD4+ T cell tolerance. doi: 10.1038/ni.2520, 46. As not all NR4As were properly studied at each differentiation steps of CD8+ T cells, a full understanding of their respective role during acute CD8+ T cell response await further studies. Kim, Y.C. The transcription of Nr4a2 is highly enriched in peripheral blood T cells of multiple sclerosis (MS) patients and in T cells during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS (114, 116). J Exp Med (1996) 184:923–30. Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77. Interestingly, the DARs less accessible in NR4A triple-deficient TILs are very similar to those more open in CD8+ T cells expressing the exhaustion-inducing engineered form of NFAT that cannot interact with AP-1 (CA-RIT-NFAT) (47, 48, 96). While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. It was shown that NR4A and TOX transcription factors act downstream of NFAT to induce the transcriptional program of exhaustion. ; Biden, T.J. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Boddupalli et al. doi: 10.4049/jimmunol.177.10.6660, 39. This requires that developing thymocytes undergo an education process during their differentiation. doi: 10.1016/j.jneuroim.2006.02.004, 117. Williams MA, Ravkov EV, Bevan MJ. doi: 10.1073/pnas.2007224117, 90. Cell (2015) 163:975–87. J Biol Chem (2010) 285:11827–35. Further studies should be done to determine which signals mediate the expression of NR4A family members in CD8+ Trm cells and how they play a role in Trm cell differentiation. doi: 10.1046/j.1440-1711.1998.00709.x, 53. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells. Studies showing that Nr4a gene transcription was induced in thymocytes by TCR signaling raised the possibility that this could similarly occur in mature CD8+ T cells. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy. ; Penn, L.Z. J Immunol (2017) 198:657–68. ; Goode, J.M. Schietinger, A.; Greenberg, P.D. Overall this suggests that NR4As directly contribute to the regulation of genes involved in CD8+ T cell exhaustion and explains why their deletion reduces T cell exhaustion. Gill, G. Post-translational modification by the small ubiquitin-related modifier SUMO has big effects on transcription factor activity. Nkx6.1, a key β-cell transcription factor upregulates Nr4a1 and Nr4a3 expression. NR4A3-C (C-terminal 308 amino acids of NR4A3) fused with a flag tag in the N-terminal and SMARCB1 fused with an HA tag in the N-terminal were coexpressed in HEK-293T cells, followed by an antiflag IP assay. ; Glander, S.; Schadlich, M.; Kuhlencord, M.; Daber, N.M.; et al. Hu, Y.; Zhan, Q.; Liu, H.-X. Figure 1 Function of the NR4A family in thymocyte development. Graded Levels of IRF4 Regulate CD8+ T Cell Differentiation and Expansion, but Not Attrition, in Response to Acute Virus Infection. However, deficiency in Bim alone impaired clonal deletion in this model (62), suggesting that in this case NR4A1 is not sufficient to drive clonal deletion independently of Bim, lending further support for NR4A transcriptional activity as the major modulator of thymocyte fate. ; Call, S.G.; Nguyen, L.; Freire, P.R. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. doi: 10.1210/me.2010-0015, 4. Nature (2016) 537:417–21. Endocrinology (2007) 148:34–44. Cell Death Differ (2016) 23:1804–14. In harmony with this assertion, overexpression of full-length NR4A1 or NR4A3 (but not NR4A2) induced thymocyte apoptosis in vivo, while that of the NR4A1 dominant negative did not (12, 27, 30, 41) but this assumes that the dominant negative NR4A1 mutant only impairs the transcriptional activity of NR4A1. ; Cleasby, M.E. In thymocytes, protein kinase C (not AKT, JNK, ERK1/2 or p38) is thought to phosphorylate both NR4A1 and NR4A3, leading to mitochondrial translocation (59), yet both MAPK and PI3K inhibitors have been shown to inhibit this phenomenon specifically in SP thymocytes in a separate study (38). H460 and Calu-6 cells overexpressing Nr4a1 had greater BrdU incorporation and Nr4a1 knockdown inhibited H460 cell growth [, Nr4a1 has also been specifically identified to induce proliferation in colorectal cancer, renal cancer, medulloblastomas and thyroid cancer. Nat Immunol (2019) 20:326–36. doi: 10.1128/mcb.20.22.8382-8389.2000, 64. ; Chau, T.; Li, Y.; Yvonne Wan, Y.-J. Fedorova, O.; Petukhov, A.; Daks, A.; Shuvalov, O.; Leonova, T.; Vasileva, E.; Aksenov, N.; Melino, G.; Barlev, N.A. Ruaud, A.F. EMBO J (2015) 34:2042–58. Angiogenesis is also linked to the Nr4a subfamily, making it another target to limit tumor growth. NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPalpha and inflammatory signaling. All authors contributed to the article and approved the submitted version. Cloning and structural organization of the gene encoding the murine nuclear receptor transcription factor, NURR1. H. These data clearly indicate that the Nr4as play a critical role in regulating apoptosis across several different tissues. ; Kleijer, M.; Weijer, K.; ten Brinke, A.; Roelofs, H.; Van Tiel, C.M. Klein L, Kyewski B, Allen PM, Hogquist KA. ; Brown, L.F.; Nagy, J.A. Pearen, M.A. At the memory stage, the Nr4a transcription was shown to be enriched in a particular subset of memory CD8+ T cells, the resident memory CD8+ T cells (Trm). Within the differentially accessible regions (DARs) that are less open in Nr4a3−/− CD8+ T cells, there was an expected enrichment for the NBRE motif, which suggests that several genes within these regions are direct targets of NR4A3. In agreement with a role for NR4A1 in regulating T cell metabolism was the regulation of several genes involved in T cell metabolism such as electron transport genes and genes controlling glucose metabolism. ; van Weeghel, M.; Huveneers, S.; Vos, M.; Evers-van Gogh, I.J. Thompson J, Winoto A. ; Bruey-Sedano, N.; Cao, X.; Lin, B.; Lin, F.; Han, Y.H. Furthermore, NR4A1 was shown to bind to the Esrra gene, encoding for ERRα. TB and NL edited the manuscript. The comparison of the transcriptome of NR4A1 overexpressing CD4+ T cells and CD4+ tolerant T cells revealed a common gene signature containing a core cluster of genes controlling T cell activation or dysfunction. ; Youn, H.D. Veillette A, Bookman MA, Horak EM, Bolen JB. Subsequent studies showed that the severity of T cell exhaustion typically correlated with the number of inhibitory receptors that were co-expressed. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Identification of a new brain-specific transcription factor, NURR1. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. ; Guo, L.; Zhang, X.; Ma, Y.; Zhou, Y. Overexpression of oxidored-nitro domain containing protein 1 induces growth inhibition and apoptosis in human prostate cancer PC3 cells. The dispensability of NR4A1 for UbsA-mediated clonal deletion was further reinforced by a study using the physiological HYcd4 transgenic TCR model (18). Aire regulates negative selection of organ-specific T cells. In summary, NR4A1 modulates the transcriptional program of CD4+ T cells by directly upregulating the expression of target genes containing NBRE motifs while downregulating the expression of AP-1 target genes (88). ; Zhao, B.X. Eur J Immunol (2010) 40:2041–9. Nur77 deletion impairs muscle growth during developmental myogenesis and muscle regeneration in mice. Immunity (2000) 12:537–46. Corrocher, F.A. Hirano T(1), Nagasaki-Maeoka E(1), Ishizuka Y(1), Takatori A(2), Watanabe Y(1), Hoshi R(1), Yoshizawa S(1), Kawashima H(1), Uekusa S(1), Sugito K(1), Uehara S(1), Fukuda N(3), Nagase H(4), Takayama T(5), Soma M(5)(6), Koshinaga T(1), Fujiwara K(7)(8).
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