Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization

Sarraf, Shireen A.; Raman, Malavika; Guarani-Pereira, Virginia; Sowa, Mathew E.; Huttlin, Edward L.; Gygi, Steven P.; Harper, J. Wade

doi:10.1038/nature12043

Cited by 892 publications

(930 citation statements)

References 33 publications

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“…8 This is in agreement with the observed increase in parkin levels upon Rpn13 silencing (Fig. 5A), increased parkin stability upon removal of its Ubl domain (58), and lack of strong increase in proteasomal binding to parkin lacking Ubl domain upon mitochondrial depolarization (56). Rpn13 might also regulate the amount of parkin depending on the availability of parkin substrates and might recruit parkin for its subsequent degradation when its substrates are not available or are present at low amounts.…”

Section: Discussionsupporting

confidence: 87%

“…Thus, at least for these substrates, parkin binding to the proteasome may not be essential for turnover. However, the role of parkin in turnover of other substrates could not be excluded, and we therefore tested the effect of HEK293T knockdown in the context of mitophagy, where the role of parkin has been well established (13,22,24,56). Indeed, Rpn13 knockdown caused a delay in the clearance of the outer mitochondrial protein TOM20 upon CCCP treatment.…”

Section: Discussionmentioning

confidence: 99%

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

Aguileta

Korać

Durcan

et al. 2015

Journal of Biological Chemistry

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Background:The role of the N-terminal ubiquitin-like domain of the E3 ligase parkin is not fully understood. Results: Parkin is recruited to the 26 S proteasome through the interaction of its ubiquitin-like domain with the intrinsic proteasomal ubiquitin receptor Rpn13. Conclusion: Parkin turnover and E3 ligase activity can be regulated by its recruitment to the 26 S proteasome via Rpn13. Significance: Parkin-Rpn13 interaction might be exploited as a potential therapeutic strategy.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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

Aguileta

Korać

Durcan

et al. 2015

Journal of Biological Chemistry

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“…An unanswered question is why Parkin E3 ligase activity is required for mitochondrial translocation. In our studies, we found that, unlike the WT RBR domain, a mitochondrially- [44]. Another recent study reported a new function for Parkin showing that in response to cellular stress, Parkin is recruited to the linear ubiquitin chain assembly complex, and increases linear ubiquitylation of NEMO, a process that is critical for the activation of the NF-κB pathway [45].…”

Section: Parkin Binds K63-linked Ubiquitin Chainssupporting

confidence: 53%

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Zheng

Hunter

2013

Cell Res

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Pink1, a mitochondrial kinase, and Parkin, an E3 ubiquitin ligase, function in mitochondrial maintenance. Pink1 accumulates on depolarized mitochondria, where it recruits Parkin to mainly induce K63-linked chain ubiquitination of outer membrane proteins and eventually mitophagy. Parkin belongs to the RBR E3 ligase family. Recently, it has been proposed that the RBR domain transfers ubiquitin to targets via a cysteine~ubiquitin enzyme intermediate, in a manner similar to HECT domain E3 ligases. However, direct evidence for a ubiquitin transfer mechanism and its importance for Parkin's in vivo function is still missing. Here, we report that Parkin E3 activity relies on cysteinemediated ubiquitin transfer during mitophagy. Mutating the putative catalytic cysteine to serine (Parkin C431S) traps ubiquitin, and surprisingly, also abrogates Parkin mitochondrial translocation, indicating that E3 activity is essential for Parkin translocation. We found that Parkin can bind to K63-linked ubiquitin chains, and that targeting K63-mimicking ubiquitin chains to mitochondria restores Parkin C431S localization. We propose that Parkin translocation is achieved through a novel catalytic activity coupled mechanism.

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“…Moreover, the regulation of FBXW7 by Parkin suggests a putative feedback loop providing regulatory countermeasures. Although further work will be required to elucidate these mechanisms, additional evidence supports a role for Parkin in regulating lipid metabolism; Parkin has been reported to ubiquitinate and stabilize both the SREBP target FASN and the fatty acid transporter CD36 (9,28). Finally, the identification of SREBF1 as a GWAS risk locus for sporadic PD (10), coupled with our findings that this pathway regulates mitophagy, provides further support that the causes of sporadic and autosomal recessive PD may share some mechanistic overlap.…”

Section: Discussionmentioning

confidence: 99%

“…Following loss of ΔΨm, PINK1 accumulates on the outer mitochondrial membrane (OMM) (3,4), where its kinase activity stimulates the translocation of Parkin (5, 6) from a diffuse cytoplasmic distribution to accumulate on mitochondria (7). The recruitment of Parkin to mitochondria results in the ubiquitination of multiple proteins (8,9). These include several proteins on the OMM that regulate mitochondrial dynamics, such as Mfn and Miro.…”

mentioning

confidence: 99%

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Ivatt

Sánchez-Martínez

Godena

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

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Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, termed mitophagy. We undertook a genome-wide RNAi screen as an unbiased approach to identify genes regulating the PINK1/Parkin pathway. We identified several genes that have a conserved function in promoting mitochondrial translocation of Parkin and subsequent mitophagy, most notably sterol regulatory element binding transcription factor 1 (SREBF1), Fbox and WD40 domain protein 7 (FBXW7), and other components of the lipogenesis pathway. The relevance of mechanisms of autosomal recessive parkinsonism to sporadic PD has long been debated. However, with the recent identification of SREBF1 as a risk locus for sporadic PD, our findings suggest a common mechanistic link between autosomal recessive and sporadic PD, and underscore the importance of mitochondrial homeostasis. P arkinson disease (PD) is an age-related neurodegenerative disease caused principally by the loss of midbrain dopaminergic neurons, resulting in motor disturbances, such as postural instability, resting tremor, and bradykinesia, as well as other nonmotor symptoms. Current therapeutic strategies alleviate symptoms by the replacement of dopamine, with variable efficacy and substantial side effects. However, there are currently no established curative, preventative, or disease-modifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis. Genetic analyses have identified causative mutations for autosomal dominant and recessive forms of familial parkinsonism. Functional studies of these genes have provided great insight into potential pathogenic mechanisms of inherited forms of PD; however, it is unclear how these may relate to the more common sporadic forms of PD. To gain insight into the genetic influence in sporadic PD, genome-wide association studies (GWASs) have revealed several loci that are significantly associated with the occurrence of PD, and so are considered potential risk factors. However, we lack mechanistic insight into how many of the associated risk loci may contribute to pathogenesis.Mitochondrial dysfunction has long been considered a key contributing factor in the pathogenesis of PD, with evidence from postmortem tissue, epidemiological studies, and genetics. In particular, a body of evidence indicates that two genes linked to recessive parkinsonism, PTEN-induced kinase 1 (PINK1) and parkin, act in a common pathway to regulate mitochondrial turnover, providing an attractive hypothesis for the impact of mitochondrial homeostasis on pathogenesis (1). The process of mitophagy to degrade dysfunctional mitochondria has been extensively studied using uncoupling agents to dissipate the mitochondrial membrane potential (ΔΨm) (2). Following loss of ΔΨm, PINK1 accumulates on the outer mit...

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Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization

Cited by 892 publications

References 33 publications

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

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

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

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