Disulfide isomerase glucose-regulated protein 58 is required for the nuclear localization and degradation of retinoic acid receptor alpha

Reproduction : the Official Journal of the Society for the Study of Fertility
Li ZhuKwan Hee Kim

Abstract

Retinoic acid receptor alpha (RARA) is critical for spermatogenesis, as shown by a sterility phenotype observed in Rara knockout mice. RARA is important in both Sertoli and germ cells of the testis. Here, we demonstrate that a disulfide isomerase glucose-regulated protein 58 (GRp58) participates in the nuclear import and degradation of RARA in Sertoli cells. GRp58 interacted with RARA in the presence of all-trans retinoic acid (ATRA) ligand and, as a complex, it was translocated from the cytoplasm to the nucleus and, then with time, GRp58 dissociated from RARA and was found in the cytoplasm. The GRp58 RNAi treatment disrupted ATRA-dependent RARA nuclear localization, indicating the requirement of GRp58 for RARA nuclear localization. Moreover, treatment with sulfhydryl-modifying agents that oxidize SH-groups of cysteine residues to disulfide bonds abolished ATRA-mediated RARA nuclear localization, suggesting that the thiol oxidoreductase activity of GRp58 may be required for RARA nuclear import. Additionally, the proteasome inhibitor treatment resulted in the co-localization of GRp58 and RARA at the endoplasmic reticulum (ER), suggesting that GRp58 may bring RARA to the ER for the ER-associated degradation (ERAD) of RARA before ...Continue Reading

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Citations

Jul 6, 2013·Mutation Research·Hongyan LiYang He
Dec 21, 2012·Molecular Carcinogenesis·Antoine MénoretDaniel W Rosenberg
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Jul 21, 2017·Pharmacology & Therapeutics·Aubryanna HettinghouseChuan-Ju Liu
May 18, 2021·Frontiers in Genetics·Meimiao FangLiang Chen

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