Nur77 Signaling in T Lymphocytes


Pathway Description

During development in the thymus, immature thymocytes which express self-reactive TCRs are eliminated from the developing T cell repertoire. The process of clonal deletion or negative selection is mediated by apoptotic signals delivered to thymocytes. This mechanism is crucial for generating a peripheral T cell population which recognizes only foreign pathogens rather than self-antigens which could lead to autoimmunity. Among the proteins that are induced by TCR signaling is Nur77 which is crucial for TCR-mediated thymocyte apoptosis. Nur77 is an inducible orphan nuclear receptor which is often implicated in apoptosis, particularly in T cells, thymocytes, and tumor cells. It is a phosphoprotein, composed of an N-terminal AF1 transactivation domain, a central terminal DNA-binding domain with two zinc fingers and a C-terminal ligand-binding domain. Two separate mechanisms account for the pro-apoptotic activities of Nur77: 1) Its DNA-binding and transactivation abilities, and 2) Translocation to mitochondria.Maximal induction of Nur77 in thymocytes and T cells requires combined signals from the TCR-CD3 complex activated by antigens and additional co-stimulation signals from ligand-activated CD28. Nur77 transcription is regulated by a complex web of transcription factors and other regulatory proteins. MADS box transcription Enhancer Factor-2 (MEF2) is the major transcription factor responsible for Ca2+ dependent Nur77 transcription. In T cells, MEF2D is the dominant family member. Several repressors and activators are associated with MEF2D. In resting cells, Cabin1, a calcineurin interacting repressor protein remains associated with MEF2D and represses its transcriptional activity. This repression is relieved by calmodulin which is activated by an increase in intracellular Ca2+. The HDAC-like protein MITR also participates in repression of MEF2D which is relieved by calmodulin. MEF2D is a weak transcription factor and dissociation of various repressors from MEF2D in activated T cells is not sufficient for it to activate Nur77 transcription. Through a DNA-independent mechanism, NFAT2 can co-activate MEF2D DNA elements. In addition, ERK5 can also associate with MEF2D and potently activate transcription. All these events lead to the transcription of Nur77. Nur77 then brings about apoptosis by activating apoptotic genes like FasL and CD30 which are the major downstream effectors for Nur77 in thymocytes.

Nur77 induces apoptosis another distinct way by direct binding of BCL2 inside mitochondria and allosteric reversal of BCL2's activity from anti- to pro-apoptotic, prompting mitochondrial release of cytochrome C, caspase activation, and apoptosis. Nur77 is targeted to mitochondria following regulated phosphorylation by PKC and other kinases, as well as heterodimerization with RXRα. 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. (Upgraded 03/2020)


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