PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis

Saita, Shotaro; Nolte, Hendrik; Fiedler, Kai Uwe; Kashkar, Hamid; Venne, A. Saskia; Zahedi, René P.; Krüger, Marcus; Langer, Thomas

doi:10.1038/ncb3488

Cited by 123 publications

(149 citation statements)

References 68 publications

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“…Intriguingly, Skd3 is cleaved by the inner-membrane rhomboid protease, PARL, at amino acid 127, between the 35-amino acid, hydrophobic stretch and the ankyrin-repeat domain ( Fig. S5a) (Saita et al, 2017;Spinazzi et al, 2019). Sequence analysis shows that the Skd3 35-amino acid, hydrophobic stretch and the PARL-cleavage motif are both highly conserved among mammalian species (Fig.…”

Section: Skd3 Disaggregase Activity Is Enhanced By Parl Cleavagementioning

confidence: 99%

Skd3 (humanCLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Cupo

Shorter

2020

Preprint

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Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human CLPB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 dissolves α-synuclein fibrils connected to Parkinson's disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity. Thus, Skd3 is a potent protein disaggregase critical for human health.

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Section: Skd3 Disaggregase Activity Is Enhanced By Parl Cleavagementioning

confidence: 99%

Skd3 (humanCLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Cupo

Shorter

2020

Preprint

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“…Similarly, in humans with type 2 diabetes, PARL mRNA and mitochondrial DNA are reduced in skeletal muscle. PARL was recently identified as a pro-apoptotic protease because it cleaves mitochondrial Smac/DIABLO [84]. The processed protein is released into the cytosol and binds an apoptosis inhibitor, thereby triggering the caspase cascade.…”

Section: Regulation Of Physiological Processesmentioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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“…PARL has also been implicated in the regulation of apoptotic signaling through OPA1 processing (Pellegrini and Scorrano, 2007) and other mechanisms involved in regulating cristae morphology and cytochrome c release (Cipolat et al, 2006; Frezza et al, 2006). In addition, PARL processes the pro-apoptotic SMAC/Diablo to release this pro-apoptotic factor to the cytosol (Saita et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

Coordinating Mitochondrial Biology Through the Stress-Responsive Regulation of Mitochondrial Proteases

Lebeau

Rainbolt

Wiseman

2018

International Review of Cell and Molecular Biology

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Proteases are localized throughout mitochondria and function as critical regulators of all aspects of mitochondrial biology. As such, the activities of these proteases are sensitively regulated through transcriptional and post-translational mechanisms to adapt mitochondrial function to specific cellular demands. Here, we discuss the stress-responsive mechanisms responsible for regulating mitochondrial protease activity and the implications of this regulation on mitochondrial function. Furthermore, we describe how imbalances in the activity or regulation of mitochondrial proteases induced by genetic, environmental, or aging-related factors influence mitochondria in the context of disease. Understanding the molecular mechanisms by which cells regulate mitochondrial function through alterations in protease activity provide insights into the contributions of these proteases in pathologic mitochondrial dysfunction and reveals new therapeutic opportunities to ameliorate this dysfunction in the context of diverse classes of human disease.

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PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis

Cited by 123 publications

References 68 publications

Skd3 (humanCLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Skd3 (humanCLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Proteases: Pivot Points in Functional Proteomics

Coordinating Mitochondrial Biology Through the Stress-Responsive Regulation of Mitochondrial Proteases

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