Nuclear Parkin Activates the ERRα Transcriptional Program and Drives Widespread Changes in Gene Expression Following Hypoxia

• Published in: Scientific reports 2020-05, Vol.10 (1), p.8499-8499, Article 8499
• Main Authors: Shires, Sarah E., Quiles, Justin M., Najor, Rita H., Leon, Leonardo J., Cortez, Melissa Q., Lampert, Mark A., Mark, Adam, Gustafsson, Åsa B.
• Format: Article
• Language: English
• Subjects: 631/337; 631/80; 692/4019; 692/699; Animals; Cell Nucleus - genetics; Cell Nucleus - metabolism; ERRalpha Estrogen-Related Receptor; Estrogens; Female; Gene expression; Gene Expression Regulation; HeLa Cells; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia - physiopathology; Immunoprecipitation; Kinases; Male; Metabolic pathways; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitophagy; Movement disorders; multidisciplinary; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Neurodegenerative diseases; Parkin protein; Parkinson's disease; Protein-serine/threonine kinase; Proteins; Proteomics; PTEN-induced putative kinase; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Science; Science (multidisciplinary); Transcriptome; Transgenic mice; Translocation; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - physiology; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-65438-7

Parkin is an E3 ubiquitin ligase well-known for facilitating clearance of damaged mitochondria by ubiquitinating proteins on the outer mitochondrial membrane. However, knowledge of Parkin’s functions beyond mitophagy is still limited. Here, we demonstrate that Parkin has functions in the nucleus and that Parkinson’s disease-associated Parkin mutants, ParkinR42P and ParkinG430D, are selectively excluded from the nucleus. Further, Parkin translocates to the nucleus in response to hypoxia which correlates with increased ubiquitination of nuclear proteins. The serine-threonine kinase PINK1 is responsible for recruiting Parkin to mitochondria, but translocation of Parkin to the nucleus occurs independently of PINK1. Transcriptomic analyses of HeLa cells overexpressing wild type or a nuclear-targeted Parkin revealed that during hypoxia, Parkin contributes to both increased and decreased transcription of genes involved in regulating multiple metabolic pathways. Furthermore, a proteomics screen comparing ubiquitinated proteins in hearts from Parkin −/− and Parkin transgenic mice identified the transcription factor estrogen-related receptor α (ERRα) as a potential Parkin target. Co-immunoprecipitation confirmed that nuclear-targeted Parkin interacts with and ubiquitinates ERRα. Further analysis uncovered that nuclear Parkin increases the transcriptional activity of ERRα. Overall, our study supports diverse roles for Parkin and demonstrates that nuclear Parkin regulates transcription of genes involved in multiple metabolic pathways.