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Extra-Nuclear and Nuclear Rarα Reciprocally Control Tcr-Induced Proliferation and Differentiation

45 Pages Posted: 22 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Alexandre Larange

Alexandre Larange

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Kiyokazu Kakugawa

RIKEN Center for Integrative Medical Sciences

Ikuo Takazawa

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Hitoshi Iwaya

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

SooMun Ngoi

University of California, San Diego (UCSD) - Department of Medicine

Laetitia Seguin

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Ildefonso Vicente-Suarez

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Nicolas Thiault

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Stephane Becart

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Cell Biology

Christopher Lena

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Yujun Huang

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Sonia Feau

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Jr-Wen Shui

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Benjamin J. Schmiedel

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Amnon Altman

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Cell Biology

Bjoern Peters

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Pandurangan Vijayanand

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Bjorn Lillemeier

Salk Institute for Biological Studies - Immunobiology and Microbial Pathogenesis Laboratory

John T. Chang

University of California, San Diego (UCSD) - Department of Medicine

Ichiro Taniuchi

RIKEN Center for Integrative Medical Sciences - Laboratory for Transcriptional Regulation

Mitchell Kronenberg

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Hilde Cheroutre

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

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Abstract

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

Suggested Citation

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 is a paper under consideration at Cell Press and has not been peer-reviewed.

Alexandre Larange

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Kiyokazu Kakugawa

RIKEN Center for Integrative Medical Sciences

1-7-22, Suehiro-cho
Tsurumi-ku
Yokohama, Kanagawa
Japan

Ikuo Takazawa

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Hitoshi Iwaya

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

SooMun Ngoi

University of California, San Diego (UCSD) - Department of Medicine

9500 Gilman Drive
La Jolla, CA 92093
United States

Laetitia Seguin

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Ildefonso Vicente-Suarez

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Nicolas Thiault

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Stephane Becart

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Cell Biology

9420 Athena Cir
La Jolla, CA 92037
United States

Christopher Lena

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Yujun Huang

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Sonia Feau

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Jr-Wen Shui

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Benjamin J. Schmiedel

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

9420 Athena Cir
La Jolla, CA 92037
United States

Amnon Altman

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Cell Biology

9420 Athena Cir
La Jolla, CA 92037
United States

Bjoern Peters

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

9420 Athena Cir
La Jolla, CA 92037
United States

Pandurangan Vijayanand

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

La Jolla, CA 92037
United States

Bjorn Lillemeier

Salk Institute for Biological Studies - Immunobiology and Microbial Pathogenesis Laboratory

10010 North Torrey Pines Road
La Jolla, CA 92037
United States

John T. Chang

University of California, San Diego (UCSD) - Department of Medicine

9500 Gilman Drive
La Jolla, CA 92093
United States

Ichiro Taniuchi

RIKEN Center for Integrative Medical Sciences - Laboratory for Transcriptional Regulation

1-7-22, Suehiro-cho
Tsurumi-ku
Yokohama, Kanagawa
Japan

Mitchell Kronenberg

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Hilde Cheroutre (Contact Author)

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology ( email )

9420 Athena Cir
La Jolla, CA 92137
United States

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