The E3 Ubiquitin Ligase Parkin Is Recruited to the 26 S Proteasome via the Proteasomal Ubiquitin Receptor Rpn13

Aguileta, Miguel; Korać, Jelena; Durcan, Thomas M.; Trempe, Jean‐François; Haber, Michael; Gehring, Kalle; Elsasser, Suzanne; Waidmann, Oliver; Fon, Edward A.; Husnjak, Koraljka

doi:10.1074/jbc.m114.614925

Cited by 35 publications

(38 citation statements)

References 61 publications

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“…To determine whether, similar to autophagy, mitophagy also affects CSCs, we treated HepG2 cells with Mdivi-1, a mitophagy inhibitor (Cui et al, 2010), and carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitophagy inducer (Ding et al, 2012). As shown in Figure S5A, Mdivi-1 increased TOM20 and TIM23 protein levels, which are translocases associated with mitochondrial outer and inner membranes, respectively (Aguileta et al, 2015). It also decreased the levels of mitochondrion-associated LC3-II and PINK1, a protein kinase important for the initiation of mitophagy (Youle and Narendra, 2011), confirming its ability to suppress mitophagy.…”

Section: Resultsmentioning

confidence: 99%

Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells

Li¹,

et al. 2017

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Summary Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When mitophagy is enhanced, p53 colocalizes with mitochondria and is removed by a mitophagy-dependent manner. However, when mitophagy is inhibited, p53 is phosphorylated at serine-392 by PINK1, a kinase associated with mitophagy, on mitochondria and translocated into the nucleus where it binds to the NANOG promoter to prevent OCT4 and SOX2 transcription factors from activating the expression of NANOG, a transcription factor critical for maintaining the stemness and the self-renewal ability of CSCs, resulting in the reduction of hepatic CSC populations. These results demonstrate that mitophagy controls the activities of p53 to maintain hepatic CSCs and provide an explanation to why autophagy is required to promote hepatocarcinogenesis.

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Section: Resultsmentioning

confidence: 99%

Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells

Li¹,

et al. 2017

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“…This affinity attracts the proteasome to mitochondria and facilitates the proteasomal degradation of selected OM proteins and PARKIN itself [89]. The OM-localized DUB Usp30 negatively regulates PARKIN-mediated mitophagy by removing ubiquitin conjugates from OM proteins.…”

Section: Ubiquitin–proteasome System Components Localized To Mitochonmentioning

confidence: 99%

Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

2017

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Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin–proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level.

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“…The Ub conjugates on PARKIN are confined to Lys27, Lys48, and Lys76 in its N-terminal Ubl domain (Sarraf et al 2013;Durcan et al 2014). Ubiquitination at these sites may regulate the interaction of the Ubl with more C-terminal domains of PARKIN (Chaugule et al 2011) as well as with other Ubl-and Ub-binding proteins (Fallon et al 2006;Trempe et al 2009;Aguileta et al 2015). Thus, autoubiquitination of the PARKIN Ubl may act as a second PTM that, in concert with phosphorylation, acts as an added layer of regulation to control PARKIN activity and mitochondrial recruitment.…”

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confidence: 99%

The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

2015

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Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ubdependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKINmediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1-PARKIN pathway will be critical for our understanding of mitochondrial quality control.Phosphorylation and ubiquitination are two post-translational modifications (PTMs) that often occur together in the regulation of signaling cascades. Examples of pathways regulated by both include the epidermal growth factor (EGF) receptor and NFκB signaling pathways (Karin and Ben-Neriah 2000;Nguyen et al. 2013). Typically, the addition of a phosphate moiety onto a particular residue of a substrate protein regulates the ability of an E3-ubiquitin (Ub) ligase to attach Ub onto lysine residues within a substrate (Lin et al. 2002;Gallagher et al. 2006;Dou et al. 2012). Considering the prominent cross-talk between these PTMs, it is not surprising that they are also implicated in many disease-associated pathways, including cancer and neurodegenerative diseases such as Parkinson's disease (PD). PD is a progressive neurodegenerative disorder that in most cases occurs sporadically. However, the discovery of genes responsible for rare familial cases of PD has shed light on the pathogenesis of the disease. For instance, recessive loss-of-function mutations in the PARK2 and PARK6 genes encode the E3-Ub ligase PARKIN and the mitochondrially targeted kinase PINK1, respectively. These two proteins act together through an intricate int...

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The E3 Ubiquitin Ligase Parkin Is Recruited to the 26 S Proteasome via the Proteasomal Ubiquitin Receptor Rpn13

Cited by 35 publications

References 61 publications

Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells

Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells

Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

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