<scp>USP</scp>
            30 deubiquitylates mitochondrial
            <scp>P</scp>
            arkin substrates and restricts apoptotic cell death

Liang, Jinrui; Amador, Martínez; Lane, Jon D.; Mayor, Ugo; Clague, Michael J.; Urbé, Sylvie

doi:10.15252/embr.201439820

Cited by 140 publications

(159 citation statements)

References 32 publications

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“…It should be noted that USP30 was also overexpressed in the USP15 study, but no effect on mitophagy was observed (Cornelissen et al 2014). Moreover, in addition to its role in regulating mitophagy, USP30 has recently been shown to deubiquitinate substrates of PARKIN in mitochondrial cell death pathways (Liang et al 2015). Intriguingly, as with USP8, USP30 demonstrates a preference for chains with K6 linkages, hydrolyzing them at a faster rate compared with chains linked through one of the other lysines (Ordureau et al 2014;Cunningham et al 2015).…”

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confidence: 85%

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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confidence: 85%

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

2015

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“…Using these cells, it has been demonstrated that mitophagy is significantly delayed in cells expressing K6R or K63R mutant ubiquitin (Ordureau et al, 2015a). The mitochondrion-localized DUB USP30 counteracts inappropriate ubiquitylation of healthy mitochondria (Bingol et al, 2014;Cunningham et al, 2015;Liang et al, 2015;Wang et al, 2015). Interestingly, USP30 preferentially removes K6 and K11 linkages from MOM proteins (Cunningham et al, 2015).…”

Section: K6 Linkages -Still Much To Learnmentioning

confidence: 99%

Ubiquitin chain diversity at a glance

Akutsu

Đikić

Bremm

2016

Journal of Cell Science

414

367

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Ubiquitin plays an essential role in modulating protein functions, and deregulation of the ubiquitin system leads to the development of multiple human diseases. Owing to its molecular features, ubiquitin can form various homo-and heterotypic polymers on substrate proteins, thereby provoking distinct cellular responses. The concept of multifaceted ubiquitin chains encoding different functions has been substantiated in recent years. It has been established that all possible ubiquitin linkage types are utilized for chain assembly and propagation of specific signals in vivo. In addition, branched ubiquitin chains and phosphorylated ubiquitin molecules have been put under the spotlight recently. The development of novel technologies has provided detailed insights into the structure and function of previously poorly understood ubiquitin signals. In this Cell Science at a Glance article and accompanying poster, we provide an update on the complexity of ubiquitin chains and their physiological relevance.

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“…Endoplasmic reticulum (ER) localization of USP19 is crucial for its function in the ERassociated degradation pathway (ERAD) (Hassink et al, 2009, but see also Lee et al, 2014, where USP19 involvement in ERAD has been questioned), secretion of misfolded proteins upon proteasome dysfunction and ER exit of membrane proteins that fold inefficiently (Perrody et al, 2016). Similarly, USP30, which is localized to the mitochondrial outer membrane, regulates mitochondrial morphology (Nakamura and Hirose, 2008) and has been implicated in Parkin-mediated mitophagy (Bingol et al, 2014;Liang et al, 2015). In the same manner, nucleolar localization of USP36 allows it to specifically interact with and deubiquitylate a nucleolar pool of c-Myc , whereas endosomelocalized AMSH and USP8 regulate the lysosomal degradation and recycling of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) (Clague and Urbe, 2017;Millard and Wood, 2006).…”

Section: Localization-dependent Dub Functionsmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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USP 30 deubiquitylates mitochondrial P arkin substrates and restricts apoptotic cell death

Cited by 140 publications

References 32 publications

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

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

Ubiquitin chain diversity at a glance

Mechanisms of regulation and diversification of deubiquitylating enzyme function

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