The antagonistically bifunctional retinoid oxidoreductase complex is required for maintenance of all-trans-retinoic acid homeostasis

Academic Article

Abstract

  • © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. All-trans-retinoic acid (RA), a bioactive derivative of vitamin A, exhibits diverse effects on gene transcription and nongenomic regulatory pathways. The steady-state levels of RA are therefore tightly controlled, but the mechanisms responsible for RAhomeostasis are not fully understood.Wereport a molecular mechanism that allows cells to maintain a stable rate of RA biosynthesis by utilizing a biological circuit generated by a bifunctional retinoid oxidoreductive complex (ROC). We show that ROC is composed of at least two subunits of NAD-dependent retinol dehydrogenase 10 (RDH10), which catalyzes the oxidation of retinol to retinaldehyde, and two subunits of NADPHdependent dehydrogenase reductase 3 (DHRS3), which catalyzes the reduction of retinaldehyde back to retinol. RDH10 and DHRS3 also exist as homo-oligomers. When complexed, RDH10 and DHRS3 mutually activate and stabilize each other. These features ofROCensure that the rate of RA biosynthesis in whole cells is largely independent of the concentration of the individualROCcomponents.ROCoperates in various subcellular fractions including microsomes, mitochondria, and lipid droplets; however, lipid droplets display weaker mutual activation between RDH10 and DHRS3, suggesting reduced formation of ROC. Importantly, disruption of the ROC-generated circuit by a knockdown of DHRS3 results in an increased flux through the RA biosynthesis pathway and elevated RA levels despite the decrease in RDH10 protein destabilized by the absence ofDHRS3,hence demonstrating a loss of control. Thus, the bifunctional nature ofROCprovides the RA-based signaling system with robustness by safeguarding appropriate RA concentration despite naturally occurring fluctuations in RDH10 and DHRS3.
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    Digital Object Identifier (doi)

    Author List

  • Belyaeva OV; Adams MK; Wu L; Kedishvili NY
  • Start Page

  • 5884
  • End Page

  • 5897
  • Volume

  • 292
  • Issue

  • 14