A mammalian pexophagy target

Subramani, Suresh

doi:10.1038/ncb3253

Cited by 19 publications

(31 citation statements)

References 15 publications

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“…Several questions remain to be addressed, however, and it will be interesting to compare differences in the mechanisms that regulate clearance of different organelles, such as peroxisomes and mitochondria. For example, how does the ubiquitination of PEX5 lead to pexophagy, as various residues can be ubiquitinated on PEX5 leading to different fates (Subramani, 2015). Also, though PMP70 is ubiquitinated by PEX2 during amino acid depletion conditions, it is unclear whether ubiquitination of PMP70 alone induces pexophagy.…”

Section: Selective Autophagy Of Organellesmentioning

confidence: 99%

Cleaning House: Selective Autophagy of Organelles

2017

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The selective clearance of organelles by autophagy is critical for the regulation of cellular homeostasis in organisms from yeast to humans. Removal of damaged organelles clears the cell of potentially toxic byproducts and enables reuse of organelle components for bioenergetics. Thus, defects in organelle clearance may be detrimental to the health of the cells, contributing to cancer, neurodegeneration and inflammatory diseases. Organelle-specific autophagy can clear mitochondria, peroxisomes, lysosomes, endoplasmic reticulum, chloroplasts and the nucleus. Here, we review our understanding of the mechanisms that regulate the clearance of organelles by autophagy and highlight gaps in our knowledge of these processes.

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Section: Selective Autophagy Of Organellesmentioning

confidence: 99%

Cleaning House: Selective Autophagy of Organelles

2017

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“…Another common organellophagy is pexophagy, a type of autophagy that participates in the quality control of peroxisomes, which is important to lipid metabolism and hydrogen peroxide production and degradation (Nordgren et al 2013). Several proteins that are involved in peroxisome biogenesis, e.g., peroxins (encoded by PEX genes), including Pex3, Pex5 and Pex14, are suggested to participate in macropexophagy (Sakai et al 2006; Manjithaya et al 2010; Neuhaus et al 2014; Subramani 2015). An oncoprotein, hypoxia inducible factor 2α (HIF2α), has also been indicated to induce hepatocyte pexophagy (Walter et al 2014).…”

Section: Autophagy: the Basic Processmentioning

confidence: 99%

Relevance of autophagy to fatty liver diseases and potential therapeutic applications

et al. 2017

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Autophagy is an evolutionarily conserved lysosome-mediated cellular degradation program. Accumulating evidence shows that autophagy is important to the maintenance of liver homeostasis. Autophagy involves recycling of cellular nutrients recycling as well as quality control of subcellular organelles. Autophagy deficiency in the liver causes various liver pathologies. Fatty liver disease (FLD) is characterized by the accumulation of lipids in hepatocytes and the dysfunction in energy metabolism. Autophagy is negatively affected by the pathogenesis of FLD and the activation of autophagy could ameliorate steatosis, which suggests a potential therapeutic approach to FLD. In this review, we will discuss autophagy and its relevance to liver diseases, especially FLD. In addition we will discuss recent findings on potential therapeutic applications of autophagy modulators for FLD.

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“…As of now, most of the gathered data refers to ubiquitin-dependent pexophagy and point to ubiquitin as a factor in triggering pexophagy. Although work from two groups has identified PEX5 as a putative physiological target for ROS-induced pexophagy, it is unclear how exactly this works because other sites for ubiquitylation on PEX5 have been described, each leading to different physiological fates [111]. These details remain to be sorted out.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

“…These ubiquitin-binding proteins may not be a sufficient mechanism for all physiological forms of pexophagy [111]. It was recently shown that down-regulation of PEX14 partly protects peroxisomes from NBR1-induced pexophagy [54].…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

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Autophagic degradation of peroxisomes in mammals

Zientara‐Rytter

Subramani

2016

Biochemical Society Transactions

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Peroxisomes are essential organelles required for proper cell function in all eukaryotic organisms. They participate in a wide range of cellular processes including the metabolism of lipids and generation, as well as detoxification, of hydrogen peroxide. Therefore, peroxisome homeostasis, manifested by the precise and efficient control of peroxisome number and functionality, must be tightly regulated in response to environmental changes. Due to the existence of many physiological disorders and diseases associated with peroxisome homeostasis imbalance, the dynamics of peroxisomes have been widely examined. The increasing volume of reports demonstrating significant involvement of the autophagy machinery in peroxisome removal leads us to summarize current knowledge of peroxisome degradation in mammalian cells. In this review we present current models of peroxisome degradation. We particularly focus on pexophagy -the selective clearance of peroxisomes through autophagy. We also critically discuss concepts of peroxisome recognition for pexophagy, including signaling and selectivity factors. Finally, we present examples of the pathological effects of pexophagy dysfunction and suggest promising future directions. Keywordsperoxisome; pexophagy; autophagy; pexophagy receptor/adaptorAMPK Peroxisomes and their life-cyclePeroxisomes are organelles involved in hydrogen peroxide (H 2 O 2 ) metabolism [1]. These dynamic organelles contain various enzymes such as: (1) acyl-CoA oxidase, alcohol oxidase, glycolate oxidase, urate oxidase, which are involved in reducing oxygen to H 2 O 2 as a consequence of substrate oxidation; (2) catalase, which converts H 2 O 2 to water and oxygen, as well as (3) enzymes involved in fatty acid β-oxidation [1,2]. Heterogeneity of enzymes in peroxisomes links them to multiple metabolic pathways, including the breakdown of various carboxylates, synthesis of bile acids, docosahexaenoic acid (DHA) or ether-phospholipids [3] and underlies the necessity of peroxisomes for normal cell development and physiology. Peroxisomes are the main organelles responsible for cellular metabolism of H 2 O 2 , which is a type of Reactive Oxygen Species (ROS). It is an oxidant that is toxic for cells [4,5] The physiological importance of peroxisome homeostasis is demonstrated by the existence of many physiological disorders associated with peroxisomal deficiencies or dysfunctions. Because many of them are related to peroxisome biogenesis disorders (PBDs) [11] the mechanism of peroxisome biogenesis and proliferation has been examined extensively. The focus on peroxisome homeostasis is more recent, with an emphasis on peroxisome degradation mechanisms, as a healthy peroxisome population requires not only their effective formation but also efficient removal of obsolete and dysfunctional peroxisomes. HHS Public Access Peroxisome degradation mechanismsThe estimated half-life time of mammalian peroxisomes is between 1.3-2.2 days [12][13][14][15]. This requires a balance between two processes: (1) new peroxisomes ne...

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A mammalian pexophagy target

Abstract: Protein ubiquitination in mammals is known to trigger selective autophagy of peroxisomes, through a process termed pexophagy. Until now, the peroxisomal target for pexophagy-related ubiquitination was controversial, but two studies have identified the protein PEX5 as the real candidate.

Cited by 19 publications

References 15 publications

Cleaning House: Selective Autophagy of Organelles

Cleaning House: Selective Autophagy of Organelles

Relevance of autophagy to fatty liver diseases and potential therapeutic applications

Autophagic degradation of peroxisomes in mammals

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