Nur77 Signaling in T-Cell
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Nur77 Signaling in T-Cell

During development in the thymus, immature thymocytes which express self-reactive TCR (T-Cell Receptor) are eliminated from the developing T-cell repertoire. This process of clonal deletion, or negative selection is mediated by Apoptotic signals delivered to thymocytes whose TCR have a high affinity for Self-Antigen/MHC (Major Histocompatibility Complexes)-Antigen Complexes. This mechanism is crucial for generating a peripheral T-lymphocyte population which will recognize only foreign pathogens and helps prevent unwanted immune responses which could lead to autoimmunity (Ref.1). Negative selection therefore represents a first line of defense in a battle for immunological tolerance of self. Thus, TCR-mediated thymocyte negative selection in the form of Apoptosis is important for elimination of self-reactive T-Cells. Among the proteins that are induced by TCR signaling is the Nur77, which is crucial for TCR-mediated thymocyte Apoptosis. Nur77 is an inducible Orphan Nuclear Receptor first identified as an immediate early serum-induced gene, and subsequently as a gene induced by TCR signaling in T-Cell hybridomas and immature thymocytes. It is often implicated in mediating Apoptosis, particularly in T-Cells, thymocytes, and tumor cells. It is a phosphoprotein that typically migrates between 65 and 75 kDa and is composed of an N-terminal AF1 ((Activation Function-1) transactivation domain, a central-terminal DNA-binding domain with two zinc fingers, and a C-terminal ligand-binding domain. Nur77 is constitutively active when overexpressed (Ref.2).

Two separate mechanisms account for the proapoptotic activities of Nur77: i) the proapoptotic effect of Nur77 depends on its DNA-binding and transactivation abilities, and/or ii) the translocation of Nur77 to the mitochondria is essential for its killer effect. Maximal induction of Nur77 in thymocytes and T-Cells requires combined signals from the TCR-CD3 (CD3 Antigen) complex activated by Antigens; and additional costimulation signals, from Liganld-actvated CD28 (Antigen CD28). The ligands of CD28 include:  B7-1(CD80) and B7-2 (CD86). Nur77 transcription is regulated by a complex web of transcription factors and other proteins. MEF2 (MADS Box Transcription Enhancer Factor-2) is the major transcription factor responsible for Ca2+ (Calcium)-dependent Nur77 transcription. In T-Cells, MEF2D (MADS Box Transcription Enhancer Factor-2 Polypeptide-D) is the dominant MEF2 family member. Several repressors and activators are associated with MEF2D. In resting cells, Cabin1 (Calcineurin Binding Protein-1), a Calcineurin-interacting repressor protein, remains associated with MEF2D, and represses its transcriptional activity. This repression is relieved by activated Calm (Calmodulin), which binds to Cabin1, releasing it from MEF2D (Ref.2). Cabin1 represses MEF2D transcriptional activity by two distinct mechanisms: i) First, it recruits Sin3 (Sin3 Transcriptional Regulator) along with the associated HDACs (Histone Deacetylases): HDAC1 and HDAC2, which accounts for most of its repressive activity towards MEF2D; ii) Second, it binds to MEF2D at the N-terminal domain, competes against the coactivator p300 for MEF2D binding in the absence of Ca2+ (Calcium) (Ref.3). An increase in intracellular Ca2+ leads to the dissociation of Cabin1 from MEF2D, and association of p300, which mediates transcriptional activation of MEF2D target genes. The HDAC-like protein MITR (Myocyte Enhancer-Binding Factor-2 Interacting Transcription Repressor Protein) also participates in the repression of MEF2D, which is relieved by Calm (Ref.4).

MEF2D is a weak transcription factor, and dissociation of various repressors from MEF2D in activated T-Cells is not sufficient to activate Nur77 transcription. NFAT2 (Nuclear Factor of Activated T-Cell-2), through a DNA-independent mechanism, can coactivate MEF2D DNA elements. NFAT2 is activated by Calcineurin, and enhances the transcriptional activity of MEF2D. Thus, Ca2+ signaling bifurcates, one mediated through Calm, Cabin1 and MEF2D and the other via Calm, Calcineurin, and MEF2D (Ref.3). In addition, ERK5 (Extracellular Signal-Regulated Kinase-5), a kinase with a unique C-terminal transcriptional activation domain, can also associate with MEF2D and deliver a powerful transcriptional activating activity. ERK5 is activated by the upstream MEK5. MEK5 is in turn, activated by MEKK2 (MAP/ERK Kinase Kinase-2) or MEKK3, upon TCR stimulation. All these events lead to the transcription of the proapoptotic factor, Nur77. Nur77 then brings about Apoptosis of the concerned cell by activating the Apoptotic genes. FasL (Fas Ligand) and CD30 are the major downstream effectors for Nur77 in thymocytes. The Akt/PKB (Protein Kinase-B) is a key player in transduction of Anti-Apoptotic and proliferative signals in T-Cells, and negatively regulates its Apoptotic function (Ref.5).

Translocation of Nur77 to mitochondria is another mechanism to bring about Apoptosis. Its translocation to the mitochondria is followed by the release of CytoC (Cytochrome-C) into the cytoplasm. The latter event causes activation of APAF1 (Apoptotic Protease Activating Factor-1) and Caspase9, followed by cleavage and activation of Caspase3, resulting in Apoptosis (Ref.6). Nur77 targets mitochondria through its interaction with Bcl2 (B-Cell CLL/Lymphoma-2), resulting in conversion of Bcl2 from an Anti-Apoptotic to a Pro-Apoptotic molecule. RXR ((Retinoid X Receptor) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimmerization partner of Nur77, which translocates from the nucleus to mitochondria, where it interacts with Bcl2 to induce apoptosis.  RXR-Alpha (Retinoid X Receptor-Alpha) is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimmerization that is mediated by dimmerization interfaces located in their DNA-binding domain. These effects of RXR-Alpha are attributed to a putative NES (Nuclear Export Sequence) present in its carboxyl-terminal region (Ref.2). Nur77 targets mitochondria in Prostate Cancer, Lung Cancer, Colon Cancer, Ovarian Cancer, and Gastric Cancer cells, and its mitochondrial localization is involved in Sindbis virus-induced apoptosis (Ref.7).

Apoptosis of T-Cells can be induced by multiple signaling pathways. Whereas the Fas and TNF-Alpha (Tumor Necrosis Factor-Alpha) Pathways are involved in the elimination of activated peripheral T-Cells, a distinct pathway emanating from the TCR is responsible for thymic negative selection. Orphan Steroid Receptors including Nur77 act as crucial mediators of TCR-induced Apoptosis (Ref.4). Identification and application of synthetic agonist or antagonist ligands could prove useful in clinical settings to modulate human immune responses and may lead to useful therapeutic applications (Ref.7).