UBE2N, UBE2L3 and UBE2D2/3 ubiquitin-conjugating enzymes are essential for parkin-dependent mitophagy

Geisler, Sven; Vollmer, Stefanie; Golombek, Sonia; Kahle, Philipp J.

doi:10.1242/jcs.146035

Cited by 88 publications

(75 citation statements)

References 54 publications

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“…6A). Also, in agreement with previous reports (13,18,70,71), the T240R or C431S FL Parkin mutant did not translocate to the mitochondria (Fig. 6A).…”

Section: Mutations Of the Ubl Domain Identified In Pd Patientssupporting

confidence: 94%

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

Ham¹,

Lee

Song

et al. 2016

Journal of Biological Chemistry

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Parkin is an E3 ligase that contains a ubiquitin-like (UBL)domain Parkinson disease (PD)3 is a neurodegenerative disorder that results from degenerated dopaminergic neurons in the substantia nigra. Most cases of PD are sporadic, and ϳ10% are familial (1). Gene mutations that are known to be responsible for the onset of the disease include PARK2 (Parkin), PARK6 (PINK1), PARK7 (DJ-1), LRRK2, and SNCA (␣-synuclein). LRRK2 and SNCA mutations are believed to cause PD through a gain of function, whereas PARK2, PARK6, and PARK7 mutations cause PD through a loss of function (2-4).Autosomal recessive early onset parkinsonism is linked to several loci, including PARK2 and PARK6 (5). The PARK2 gene encodes Parkin, an E3 ubiquitin ligase that consists of 465 amino acid residues. Parkin is composed of an ubiquitin-like (UBL) domain at the N terminus and a R1-in-between-ring (IBR)-Rind 2 (R2) motif at the C terminus (6 -8). Structurally, Parkin is a RING-type E3 ligase, but functionally it acts as a RING/HECT hybrid E3 ligase (9 -12). Parkin functions like a RING-type E3 ligase by interacting with E2 enzymes, UbcH7 and UbcH8, via the IBR domain, whereas the RING1 domain binds to substrates, allowing direct substrate ubiquitination. Parkin can also function like a HECT-type E3 ligase by catalyzing the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to the substrates via the active-site residues, Cys-431 and His-433. E2 enzymes that support Parkin function as a HECT-type E3 ligase are UbcH7, UbcH8, and Ubc13/Uev1a heterodimer (13,14).Substrates that are ubiquitinated by active Parkin include mitofusin (Mfn) 1 and 2, dynamin-related protein 1 (Drp1), voltage-dependent anion-selective channel protein 1 (VDAC1), mitochondrial Rho GTPase (Miro), and translocase of outer membrane 20 (TOM20) (15)(16)(17)(18)(19)(20). Parkin ligates these substrates with [21][22][23]. The substrates of Parkin with Lys-48-linked polyubiquitin chains are degraded by the ubiquitin proteasome system (23-26). However, those polyubiquitinated with Lys-63 or Lys-27 ubiquitin linkage recruit ubiquitin-binding adaptors such as histone deacetylase 6 (HDAC6) and p62/SQSTM1 (21,(27)(28)(29). The stability of Mfn1 and -2 and Drp1 are reduced by 30,31). TOM20 is both mono-and polyubiquitinated by Parkin by . In the case of VDAC1, Parkin catalyzes polyubiquitination with ubiquitin Lys-27 and Lys-63 linkages, which leads to recruitment of p62/SQSTM1 and subsequent induction of mitophagy (18,32).

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“…6A). Also, in agreement with previous reports (13,18,70,71), the T240R or C431S FL Parkin mutant did not translocate to the mitochondria (Fig. 6A).…”

Section: Mutations Of the Ubl Domain Identified In Pd Patientssupporting

confidence: 94%

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

Ham¹,

Lee

Song

et al. 2016

Journal of Biological Chemistry

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“…Mass spectrometry-based studies of mitochondria purified from CCCP-treated cells reveals a predominance of K6, K11, K48, and K63 linkages in these Ub conjugates (Ordureau et al 2014;Cunningham et al 2015). The identification of K48 and K63 linkages was not surprising, as these have been shown previously (Geisler et al 2010(Geisler et al , 2014Chan et al 2011). K48-linked Ub chains are important for proteasomal targeting, whereas K63-linked chains have been proposed to recruit autophagy adaptors.…”

Section: Mitophagy and Parkin-mediated Ubiquitinationsupporting

confidence: 56%

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 ubiquitylation of these substrates ensure the isolation of mitochondria by inhibiting fusion and promoting fission (substrates: Mfn1/2 and Drp1) (Gegg et al, 2010;Rakovic et al, 2013;Pryde et al, 2016), and by interfering with mitochondrial transport [substrate: MIRO (Mitochondrial Rho GTPase 1)] (Shlevkov et al, 2016). The formation of polyubiquitin chains has been shown to occur via K6-, K11-, K27-, K48-and K63-linkage (Geisler et al, 2010;Narendra et al, 2010;Geisler et al, 2014;Cunningham et al, 2015). While the K48-linkage is generally associated with degradation by the UPS, the roles of other types of linkage is less clear.…”

Section: Polyubiquitin Chains -Marking Mitochondria For Removalmentioning

confidence: 99%

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Zimmermann

Reichert

2017

Biological Chemistry

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Mitochondria are indispensable cellular organelles providing ATP and numerous other essential metabolites to ensure cell survival. Reactive oxygen species (ROS), which are formed as side reactions during oxidative phosphorylation or by external agents, induce molecular damage in mitochondrial proteins, lipids/ membranes and DNA. To cope with this and other sorts of organellar stress, a multi-level quality control system exists to maintain cellular homeostasis. One critical level of mitochondrial quality control is the removal of damaged mitochondria by mitophagy. This process utilizes parts of the general autophagy machinery, e.g. for the formation of autophagosomes but also employs mitophagy-specific factors. Depending on the proteins utilized mitophagy is divided into receptor-mediated and ubiquitin-mediated mitophagy. So far, at least seven receptor proteins are known to be required for mitophagy under different experimental conditions. In contrast to receptor-mediated pathways, the Pink-Parkin-dependent pathway is currently the best characterized ubiquitin-mediated pathway. Recently two additional ubiquitin-mediated pathways with distinctive similarities and differences were unraveled. We will summarize the current state of knowledge about these multiple pathways, explain their mechanism, and describe the regulation and crosstalk between these pathways. Finally, we will review recent evidence for the evolutionary conservation of ubiquitin-mediated mitophagy pathways.

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UBE2N, UBE2L3 and UBE2D2/3 ubiquitin-conjugating enzymes are essential for parkin-dependent mitophagy

Cited by 88 publications

References 54 publications

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

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

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

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