Rhomboid Protease PARL Mediates the Mitochondrial Membrane Potential Loss-induced Cleavage of PGAM5

Sekine, Shiori; Kanamaru, Yusuke; Koike, Masato; Nishihara, Ayako; Okada, Masahiro; Kinoshita, Hideyuki; Kamiyama, Manabu; Maruyama, Junichi; Uchiyama, Yasuo; Ishihara, Naotada; Takeda, Kohsuke; Ichijo, Hidenori

doi:10.1074/jbc.m112.357509

Cited by 166 publications

(234 citation statements)

References 44 publications

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“…By dephosphorylating phospho-Ub, this might enhance the accessibility of the Ub chains to DUBs and deubiquitination. One potential candidate is PGAM5, a phosphatase localized at the mitochondria that is released from the mitochondria following dissipation of the mitochondrial membrane potential (Sekine et al 2012;Chen et al 2014). Intriguingly, the presence of PGAM5 is required for PINK1 to accumulate during mitophagy, with a loss of PGAM5 reducing PINK1 levels and impairing mitophagy (Lu et al 2014).…”

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

2015

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“…Multiple isoforms of PGAM5 have been reported (5)(6)(7). The predominant isoform of PGAM5, denoted PGAM5-L, encodes a protein of 289 amino acids in which amino acids 98 -289 compose the PGAM domain.…”

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confidence: 99%

“…Both the long and short isoforms of PGAM5 contain an N-terminal mitochondrial targeting sequence that anchors the protein on the cytosolic face of the outer mitochondrial membrane (8). Proteolytic removal of the mitochondrial targeting sequence, which releases a truncated PGAM5 protein from the mitochondrial membrane, has been implicated in apoptosis and mitophagy (6,7).…”

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confidence: 99%

A Conserved Motif Mediates both Multimer Formation and Allosteric Activation of Phosphoglycerate Mutase 5

Wilkins

McConnell

Tipton

et al. 2014

Journal of Biological Chemistry

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Background: Mechanism(s) that regulate the phosphatase activity of PGAM5 are poorly understood. Results: PGAM5 contains an N-terminal WDXNWD motif required for multimerization and maximal phosphatase activity. Conclusion: PGAM5 is regulated by an intermolecular allosteric mechanism in which the assembly of PGAM5 into multimeric complexes results in robust phosphatase activity. Significance: Our data suggest a mechanism for regulating the function of PGAM5.

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“…PGAM5 has been shown to be activated in necroptosis triggering DNM1L dephosphorylation and translocation to mitochondria leading to mitochondria fragmentation (44). In addition, upon mitochondrial membrane potential loss, PGAM5 is cleaved (45), being therefore a good marker for this event. We observed that BIRO1 induced an accumulation of the cleaved PGAM-L isoform.…”

Section: Discussionmentioning

confidence: 99%

BIRO1, a Cell-Permeable BH3 Peptide, Promotes Mitochondrial Fragmentation and Death of Retinoblastoma Cells

Allaman-Pillet

Oberson

2015

Molecular Cancer Research

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Retinoblastoma is the most common pediatric intraocular neoplasm. While retinoblastoma development requires the inactivation of both alleles of the retinoblastoma tumor suppressor gene (RB1) in the developing retina, additional genomic changes are involved in tumor progression, which progressively lead to resistance of tumor cells to death. Therapeutics acting at very downstream levels of death signaling pathways should therefore be interesting in killing retinoblastoma cells. The BH3-only proteins promote apoptosis by modulating the interaction between the proand antiapoptotic members of the BCL2 protein family, and this effect can be recapitulated by the BH3 domains. This report analyzes the effect of various BH3 peptides, corresponding to different BH3-only proteins, on two retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the photoreceptor cell line 661W. The BH3 peptide BIRO1, derived from the BCL2L11 death domain, was very effective in promoting Y79 and WERI-Rb cell death without affecting the 661W photoreceptor cells. This cell death was efficient even in absence of BAX and was shown to be caspase independent. While ROS production or AIF release was not detected from mitochondria of treated cells, BIRO1 initiated mitochondria fragmentation in a short period of time following treatment.Implications: The BIRO1 peptide is highly effective at killing retinoblastoma cells and has potential as a peptidomimetic. Mol Cancer Res; 13(1); 86-97. Ó2014 AACR.

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Rhomboid Protease PARL Mediates the Mitochondrial Membrane Potential Loss-induced Cleavage of PGAM5

Cited by 166 publications

References 44 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

A Conserved Motif Mediates both Multimer Formation and Allosteric Activation of Phosphoglycerate Mutase 5

BIRO1, a Cell-Permeable BH3 Peptide, Promotes Mitochondrial Fragmentation and Death of Retinoblastoma Cells

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