Small Ubiquitin-Like Modifier-2 Modification of Retinoic Acid Receptor-α Regulates Its Subcellular Localization and Transcriptional Activity
Open accessAbstract
The retinoic acid receptor-alpha (Rara) gene is critical for germ cell development in the testis, as demonstrated by infertile Rara knockout male mice. The encoded protein for Rara (RARA) is expressed in both Sertoli cells and germ cells, but it is not always in the nucleus. Previously, all-trans retinoic acid (ATRA) was shown to increase the nuclear localization and transcriptional activity of RARA in Sertoli cells. Here, we identified a small ubiquitin-like modifier-2 (SUMO-2) modification as a novel posttranslational regulatory mechanism controlling the ATRA-dependent RARA subcellular localization and transcription. ATRA increased the SUMO-2 modification of RARA. In the presence of ATRA, lysine 166 (K166) and K171 of RARA were modified at a physiological concentration of SUMO-2, whereas in the absence of ATRA, K399 was the only site that was modified, but at a higher SUMO-2 concentration. However, K399 was critical for ATRA-controlled nuclear trafficking of RARA. In the presence of ATRA, a K399 mutation to arginine resulted in the cytoplasmic localization of K399R mutant, indicating that K166 and K171 sumoylations were inhibitory to nuclear localization. This may be due to SUMO/sentrin-specific peptidase 6 (SENP6) not being able to bind K399R mutant to desumoylate K166 and K171 in Sertoli cells, whereas it can bind RARA with intact K399. On the other hand, functional K166 and K171 sites for sumoylation were required for a full transcriptional activity, when K399 was intact. These results together suggest that both K166 and K171 sumoylation and desumoylation are critical for optimal RARA function.
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In Sertoli cells, RARα is a substrate for SUMO-2 and a dynamic process of sumoylation and desumoylation influences the cytosolic/nuclear localization of the receptor.
“Other studies demonstrated that, in Sertoli cells, RAR ␣ is a substrate for small ubiquitin-like modifi er-2 (SUMO-2) and that a dynamic process of sumoylation and desumoylation infl uences the cytosolic/nuclear localization of the receptor ( 153 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [153]
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- Authors
- Zhu, L., Santos, N. C., & Kim, K. H.
- Affiliations
- Washington State University (US)
- Corresponding author
- Kim, Kwan Hee
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2009-10-22
- Volume
- 150
- Issue
- 12
- Pages
- 5586-5595
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2795702
- OpenAlex
- W2155548073
- Cited by
- 32
- References
- 34
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2021: 1 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 3 · 2012: 1
- FWCI
- 0.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD044569, HD44569)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- retinoic acid receptor alpha, SUMO2, SUMOylation, deSUMOylation, SENP6, all-trans retinoic acid, nuclear localization, transcriptional activity, Sertoli cells, germ cell development, testis, post-translational modification, lysine modification sites
- MeSH terms
- Retinoic Acid Receptor alpha, Amino Acid Sequence, Animals, Binding Sites, Cell Line, Cell Nucleus, Chlorocebus aethiops, Humans, Lysine, Male, Molecular Sequence Data, Mutation, Protein Binding, Protein Processing, Post-Translational, Sertoli Cells, Tretinoin, Blotting, Western, Transcriptional Activation, Rats, Sprague-Dawley, Sequence Homology, Amino Acid, Receptors, Retinoic Acid, COS Cells, Reverse Transcriptase Polymerase Chain Reaction, Small Ubiquitin-Related Modifier Proteins, Rats
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