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

Li Zhu; Nadine C Santos; Kwan Hee Kim

doi:10.1530/REP-09-0527

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

Journal article

Open access

Peer reviewed

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

Li Zhu, Nadine C Santos and Kwan Hee Kim

Reproduction (Cambridge, England), Vol.139(4), pp.717-731

04/2010

DOI: https://doi.org/10.1530/REP-09-0527

Handle:

https://hdl.handle.net/2376/107627

PMID: 20130111

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Abstract

Amino Acid Sequence

Tissue Distribution - drug effects

Chlorocebus aethiops

Protein Disulfide-Isomerases - metabolism

RNA, Small Interfering - pharmacology

Cells, Cultured

Molecular Sequence Data

Rats

Male

Protein Disulfide-Isomerases - antagonists & inhibitors

Receptors, Retinoic Acid - metabolism

Rats, Sprague-Dawley

Sequence Homology, Amino Acid

Animals

Cell Nucleus - metabolism

Protein Processing, Post-Translational - drug effects

Models, Biological

COS Cells

Retinoic Acid Receptor alpha

Protein Disulfide-Isomerases - physiology

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 it is de-coupled from RARA for recycling. In this regard, proteasome inhibitor treatment also increased the interaction of RARA with UBE2J2, an ERAD-associated ubiquitin E2 enzyme. Collectively, the results indicate that GRp58 may act as a molecular chaperone that alters the protein conformation of RARA for its delivery to the nucleus and, then with time, accompanies RARA to the ER for RARA ubiquitination and proteasome-mediated ERAD.

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Title: Disulfide isomerase glucose-regulated protein 58 is required for the nuclear localization and degradation of retinoic acid receptor alpha
Creators: Li Zhu - School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, Washington 99164-4234, USA
Nadine C Santos
Kwan Hee Kim
Publication Details: Reproduction (Cambridge, England), Vol.139(4), pp.717-731
Publisher: England
Grant note: HD44569 / NICHD NIH HHS
Identifiers: 99900547194601842
Language: English
Resource Type: Journal article