Abstract
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.
Highlights
Parkin is named for its link to autosomal recessive Parkinson’s disease (PD)[8,9]
We found a significant increase in transcript levels of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PPARGC1α), Hexokinase I (HK1), Acyl-CoA Dehydrogenase Medium Chain (ACADM), and Acyl-CoA Dehydrogenase Very Long Chain (ACADVL) in HeLa cells overexpressing nuclear localization signals (NLS)-Parkin (Fig. 7b)
We uncovered that Parkin regulates gene transcription during oxygen limiting conditions, where hypoxia results in translocation of Parkin to the nucleus
Summary
Parkin is named for its link to autosomal recessive Parkinson’s disease (PD)[8,9]. loss of function mutations in Parkin contribute to loss of dopaminergic neurons, the underlying mechanisms that precipitate the neuronal degeneration associated with PD are still not fully understood. Based mostly on in vitro studies, the pathogenic phenotypes observed in Parkin-deficient cells and tissues have generally been attributed to its role in mitophagy. Emerging evidence suggests that Parkin’s functions extend beyond mitophagy and it is unlikely that mitophagy defects are solely responsible for the pathological phenotypes associated with Parkin-deficiency. As a cytosolic E3 ubiquitin ligase, Parkin has the capability of regulating numerous cellular processes through diverse protein substrates. Parkin was shown to negatively regulate inflammation via inhibition of RIPK3, an initiator of necroptosis[14]. Overall, these studies demonstrate that Parkin is a complex protein with multiple functions that contribute to cellular homeostasis and survival. Our findings demonstrate that nuclear Parkin interacts with the transcription factor ERRα to enhance its transcriptional activity
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