Ligation of nuclear retinoic acid receptors (RARs) by retinoic acid (RA) activates transcription and promotes cell differentiation. RARs can also participate in non-genomic functions in extra-nuclear spaces. Here we identify an alternative isoform of RARα expressed in the cytoplasm of T lymphocytes. Extranuclear RARα functions in T cell receptor (TCR) proximal signaling and NOTCH/c-MYC-driven proliferation. In contrast to nuclear RARα, RA negatively affects extra-nuclear RARα function in T cells. Upon activation, TCR signaling induces expression of the cellular retinoic acid binding protein 2 (CRABP2), which transports RA from the cytoplasm to the nucleus to activate nuclear RARα and at the same time sequesters RA away from extra-nuclear RARα thereby promoting TCR-driven proliferation. These data show that T cell proliferation and differentiation are reciprocally regulated by extra-nuclear and nuclear RARα and that activation-induced CRABP2 functions as a rheostat of TCR signaling via its dual control over the non-genomic and genomic actions of cytoplasmic and nuclear RARα.
Keywords: Retinoic acid receptor alpha, alternative isoform, T cell receptor, T cell proliferation, non-genomic, NOTCH, c-MYC, nuclear, extra-nuclear, CRABP, differentiation
Larange, Alexandre and Kakugawa, Kiyokazu and Takazawa, Ikuo and Iwaya, Hitoshi and Ngoi, SooMun and Seguin, Laetitia and Vicente-Suarez, Ildefonso and Thiault, Nicolas and Becart, Stephane and Lena, Christopher and Huang, Yujun and Feau, Sonia and Shui, Jr-Wen and Schmiedel, Benjamin J. and Altman, Amnon and Peters, Bjoern and Vijayanand, Pandurangan and Lillemeier, Bjorn and Chang, John T. and Taniuchi, Ichiro and Kronenberg, Mitchell and Cheroutre, Hilde, Extra-Nuclear and Nuclear Rarα Reciprocally Control Tcr-Induced Proliferation and Differentiation (February 16, 2019). Available at SSRN: https://ssrn.com/abstract=3335780 or http://dx.doi.org/10.2139/ssrn.3335780
This version of the paper has not been formally peer reviewed.
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