Back to Search
Start Over
Atypic SUMOylation of Nor1/NR4A3 regulates neural cell viability and redox sensitivity.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Sep; Vol. 35 (9), pp. e21827. - Publication Year :
- 2021
-
Abstract
- Neuron-derived orphan receptor 1, NR4A3 (Nor1)/NR4A3 is an orphan nuclear receptor involved in the transcriptional control of developmental and neurological functions. Oxidative stress-induced conditions are primarily associated with neurological defects in humans, yet the impact on Nor1-mediated transcription of neuronal genes remains with unknown mechanism. Here, we demonstrate that Nor1 is a non-conventional target of SUMO2/3 conjugation at Lys-137 contained in an atypic ψKxSP motif referred to as the pSuM. Nor1 pSuM SUMOylation differs from the canonical process with the obligate phosphorylation of Ser-139 by Ras signaling to create the required negatively charged interface for SUMOylation. Additional phosphorylation at sites flanking the pSuM is also mediated by the coordinated action of protein kinase casein kinase 2 to function as a small ubiquitin-like modifier enhancer, regulating Nor1-mediated transcription and proteasomal degradation. Nor1 responsive genes involved in cell proliferation and metabolism, such as activating transcription factor 3, cyclin D1, CASP8 and FADD-like apoptosis regulator, and enolase 3 were upregulated in response to pSuM disruption in mouse HT-22 hippocampal neuronal cells and human neuroblastoma SH-SY5Y cells. We also identified critical antioxidant genes, such as catalase, superoxide dismutase 1, and microsomal glutathione S-transferase 2, as responsive targets of Nor1 under pSuM regulation. Nor1 SUMOylation impaired gene transcription through less effective Nor1 chromatin binding and reduced enrichment of histone H3K27ac marks to gene promoters. These effects resulted in decreased neuronal cell growth, increased apoptosis, and reduced survival to oxidative stress damage, underlying the role of pSuM-modified Nor1 in redox homeostasis. Our findings uncover a hierarchical post-translational mechanism that dictates Nor1 non-canonical SUMOylation, disrupting Nor1 transcriptional competence, and neuroprotective redox sensitivity.<br /> (© 2021 Federation of American Societies for Experimental Biology.)
- Subjects :
- Animals
Apoptosis genetics
Cell Line
Cell Line, Tumor
Cell Proliferation genetics
Checkpoint Kinase 2 genetics
Gene Expression Regulation genetics
HEK293 Cells
Hippocampus metabolism
Homeostasis genetics
Humans
Mice
Neuroblastoma genetics
Neurons metabolism
Oxidation-Reduction
Oxidative Stress genetics
Phosphorylation genetics
Promoter Regions, Genetic genetics
Protein Processing, Post-Translational genetics
Transcription, Genetic genetics
Transcriptional Activation genetics
Up-Regulation genetics
Cell Survival genetics
DNA-Binding Proteins genetics
Receptors, Steroid genetics
Receptors, Thyroid Hormone genetics
Sumoylation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 35
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 34383980
- Full Text :
- https://doi.org/10.1096/fj.202100395R