Parkin Directly Modulates 26S Proteasome Activity

Um, Ji Won; Im, Eunju; Lee, Hyun Jung; Min, Boram; Yoo, Lang; Yoo, Je Hyun; Lübbert, Hermann; Stichel-Gunkel, Christine C.; Cho, Hyun Soo; Yoon, Jong Bok; Chung, Kwang Chul

doi:10.1523/jneurosci.2862-09.2010

Cited by 71 publications

(48 citation statements)

References 48 publications

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“…In contrast, we did not find any general effect of E6AP on proteasomal processivity. Parkin, a RING finger Ub ligase, has also been shown to bind the proteasome and to modulate its activity (91). However, neither UBE3C nor E6AP seemed to affect the proteasome activity itself, since siRNA knockdown of either did not alter the level of the full-length EGFP-Myc protein (Fig.…”

Section: Discussionmentioning

confidence: 98%

Identification and Proteomic Analysis of Distinct UBE3A/E6AP Protein Complexes

Martínez-Noël

Galligan

Sowa

et al. 2012

Molecular and Cellular Biology

113

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The E6AP ubiquitin ligase catalyzes the high-risk human papillomaviruses' E6-mediated ubiquitylation of p53, contributing to the neoplastic progression of cells infected by these viruses. Defects in the activity and the dosage of E6AP are linked to Angelman syndrome and to autism spectrum disorders, respectively, highlighting the need for precise control of the enzyme. With the exception of HERC2, which modulates the ubiquitin ligase activity of E6AP, little is known about the regulation or function of E6AP normally. Using a proteomic approach, we have identified and validated several new E6AP-interacting proteins, including HIF1AN, NEURL4, and mitogen-activated protein kinase 6 (MAPK6). E6AP exists as part of several different protein complexes, including the proteasome and an independent high-molecular-weight complex containing HERC2, NEURL4, and MAPK6. In examining the functional consequence of its interaction with the proteasome, we found that UBE3C (another proteasome-associated ubiquitin ligase), but not E6AP, contributes to proteasomal processivity in mammalian cells. We also found that E6 associates with the HERC2-containing high-molecular-weight complex through its binding to E6AP. These proteomic studies reveal a level of complexity for E6AP that has not been previously appreciated and identify a number of new cellular proteins through which E6AP may be regulated or functioning. E6AP was originally discovered as the cellular protein that mediates the binding of the E6 protein of the high-risk human papillomaviruses (HPVs) to the tumor suppressor p53 (35). Subsequently, E6AP was shown to catalyze the E6-dependent transfer of ubiquitin to p53, targeting it for degradation by the 26S proteasome. As such, E6AP was the first mammalian ubiquitin (Ub) ligase to be described (36,37,80).E6AP is a 100-kDa protein containing a conserved carboxyterminal domain spanning 350 amino acids, referred to as the HECT domain (homologous to E6AP carboxy terminus), that defines a family of E3 Ub ligases (34). This domain participates directly in the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to a conserved cysteine residue through a thiolester bond (34). E6AP then directs the transfer of ubiquitin from this active-site cysteine to a lysine residue of an associated substrate. Replacement of the active-site cysteine with alanine renders E6AP unable to accept ubiquitin and therefore unable to catalyze the transfer of ubiquitin to the target protein. This C/A substitution mutant is inactive and functions in a dominant-negative (DN) manner (88). Three different isoforms of E6AP that are generated by differential splicing from the same gene have been described (98). These three isoforms differ in their amino-terminal sequences, and it is not yet known whether they differ in function or substrate specificity.The E6AP protein is encoded by the UBE3A gene located in an imprinted region on chromosome 15q11-q13. As a consequence of the imprinting, only the maternal UBE3A allele is expressed in certain areas of the br...

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Section: Discussionmentioning

confidence: 98%

Identification and Proteomic Analysis of Distinct UBE3A/E6AP Protein Complexes

Martínez-Noël

Galligan

Sowa

et al. 2012

Molecular and Cellular Biology

113

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“…Several groups have shown that parkin recruitment to the 26 S proteasome via its Ubl domain increases the 26 S proteasomal activity (23,59). Recently Chaugule et al (50) found that the parkin Ubl domain inhibits its self-ubiquitination by binding to the intrinsic RING1 IBR and RING2 domains, thus keeping parkin in an inhibited state.…”

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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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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“…Studies of genes involved in heritable forms of PD, including Parkin an E3 ubiquitin ligase (12), have greatly influenced our understanding of the molecular mechanisms underlying neurodegeneration in this disorder (13). Indeed, it has been postulated that parkin mutations impair the UPS of protein degradation, leading to the accumulation of toxic misfolded or aggregated proteins (14,15). More recently, considerable attention has been focused on the role of Parkin in mitochondrial quality control (MQC) (16)(17)(18).…”

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confidence: 99%

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Rana

Rera

Walker

2013

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

291

222

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Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Longlived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusionpromoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.energy metabolism | healthspan | mitophagy | neuronal aging | proteostasis A dvanced age is a major risk factor for many neurodegenerative disorders, including both Alzheimer's disease and Parkinson disease (PD), and yet the molecular mechanisms that link aging and neurodegeneration are poorly understood. To understand this connection, it is necessary to identify the molecular events and pathways that integrate aging and neurodegenerative disease. Several lines of evidence suggest that a decline in the ability to prevent and eliminate protein misfolding (1) and impaired mitochondrial function (2) are important factors in the increased risk of disease and death associated with aging. More specifically, although the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognized (3), recent work in the nematode Caenorhabditis elegans (4-6) and the fruit fly Drosophila melanogaster (7) has shown that aging per se is associated with increased aggregation of a large number of proteins. At the same time, a decline in mitochondrial gene expression and/or energetic capacity is a hallmark of aging across diverse species (2, 8), whereas a failure to eliminate dysfunctional mitochondria has been implicated in the pathophysiology of a number of neurodegenerative diseases, including PD (9).The ubiquitin-proteasome system (UPS) is a critical component of the cellular pro...

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Parkin Directly Modulates 26S Proteasome Activity

Cited by 71 publications

References 48 publications

Identification and Proteomic Analysis of Distinct UBE3A/E6AP Protein Complexes

Identification and Proteomic Analysis of Distinct UBE3A/E6AP Protein Complexes

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

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

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