The role of ALFY in selective autophagy

Isakson, Pauline; Holland, Petter; Simonsen, Anne

doi:10.1038/cdd.2012.66

Cited by 114 publications

(83 citation statements)

References 89 publications

(115 reference statements)

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“…Based on these observations, we investigated the role of mesenchymal cell-enriched splicing factors in autophagy, a process involved in the degradation and recycling of cellular components, in particular, under cellular starvation (Matsunaga et al 2009;Isakson et al 2013;Lamb et al 2013;Baixauli et al 2014;Wild et al 2014;Khaminets et al 2016;Ktistakis and Tooze 2016). Autophagy is a dynamic process of intracellular bulk degradation in which cytosolic proteins and organelles are sequestered into double-membrane vesicles called autophagosomes, which are then fused with lysosomes for degradation and recycling.…”

Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

“…Autophagy is a dynamic process of intracellular bulk degradation in which cytosolic proteins and organelles are sequestered into double-membrane vesicles called autophagosomes, which are then fused with lysosomes for degradation and recycling. Autophagy receptors such as SQSTM1 recognize autophagic cargos and mediate formation of autophagosomes via binding to small ubiquitin-like modifiers such as MAP1LC3B and GABARAPs (Matsunaga et al 2009;Isakson et al 2013;Lamb et al 2013;Baixauli et al 2014;Wild et al 2014;Khaminets et al 2016;Ktistakis and Tooze 2016). The effect of depleting mesenchymal cell-enriched splicing factors on autophagy was tested by Western blot analysis of MAP1LC3B (whose level of lipidation can be traced by the appearance of the MAP1LC3B-II form) and of the autophagy receptor SQSTM1 which is a standard marker of cellular autophagy activity as it is degraded in the autophagosome with its cargos (Matsunaga et al 2009;Isakson et al 2013;Lamb et al 2013;Baixauli et al 2014;Wild et al 2014;Khaminets et al 2016;Ktistakis and Tooze 2016).…”

Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

“…6C-E). This includes the RUBCN gene (named KIAA0226 in FasterDB and Exon Ontology) that codes for a major autophagy inhibitor interacting with beclin 1 (BECN1) and the WDFY3 gene (also known as ALFY) that codes for an important adaptor protein for selective autophagy interacting with MAP1LC3B (also known as LC3B), SQSTM1 (also known as p62), and GABARAPs (Matsunaga et al 2009;Isakson et al 2013;Lamb et al 2013;Baixauli et al 2014;Wild et al 2014;Khaminets et al 2016;Ktistakis and Tooze 2016).…”

Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

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Identification of protein features encoded by alternative exons using Exon Ontology

et al. 2017

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Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing variation in physiological-or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named "Exon Ontology," based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encoded protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splicing. We also show that Exon Ontology helps to unravel biological processes that depend on suites of coregulated alternative exons, as we uncovered a role of epithelial cell-enriched splicing factors in the AKT signaling pathway and of mesenchymal cell-enriched splicing factors in driving splicing events impacting on autophagy. Freely available on the web, Exon Ontology is the first computational resource that allows getting a quick insight into the protein features encoded by alternative exons and investigating whether coregulated exons contain the same biological information. [Supplemental material is available for this article.]Alternative splicing is a major step in the gene expression process leading to the production of different transcripts with different exon content (or alternative splicing variants) from one single gene. This mechanism is the rule, as 95% of human genes produce at least two splicing variants (Nilsen and Graveley 2010;de Klerk and 't Hoen 2015;Lee and Rio 2015). Alternative splicing decisions rely on splicing factors binding on pre-mRNA molecules more or less close to splicing sites and regulating their recognition by the spliceosome (Lee and Rio 2015). Other mechanisms, including usage of alternative promoters and alternative polyadenylation sites, also increase the diversity of transcripts and drive both quantitative and qualitative effects (Tian and Manley 2013;de Klerk and 't Hoen 2015). Indeed, alternative promoters and alternative polyadenylation sites can impact mRNA 5 ′ -and 3 ′ -untranslated regions, which can have consequences on transcript stability or translation (Tian and Manley 2013;de Klerk and 't Hoen 2015). In addition, alternative splicing can lead to the biogenesis of nonproductive mRNAs degraded by the nonsense-mediated mRNA decay pathway (Hamid and Makeyev 2014). These mechanisms can also change the gene coding sequence. Alternative promoters and alternative polyadenylation sites can change protein N-and C-terminal domains, respec...

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Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

Section: Interplay Between Autophagy and Mesenchymal Cell-enriched Spmentioning

confidence: 99%

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Identification of protein features encoded by alternative exons using Exon Ontology

et al. 2017

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“…ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. 14 The avid reader of this collection of excellent reviews will appreciate that several major problems remain to be solved. Which are the early upstream signals triggering different types of selective autophagy?…”

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Molecular mechanisms of selective autophagy

2012

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Autophagy is the catabolic process by which the cell degrades cytoplasmic components within lysosomes. 1 The balance between the biosynthesis of cellular components and their eventual degradation is of cardinal importance for normal cellular homeostasis and health. 2 Autophagy has long been thought to be an essential but non-selective bulk degradation pathway. However, recently accumulating evidence has highlighted the selective elimination by autophagy of unwanted components such as aberrant protein aggregates, lipid droplets, dysfunctional organelles and invading pathogens.3 Some of the molecular components involved in selective autophagy have been identified, implying that we are beginning to understand how selectivity is achieved in this process. Specific autophagy receptors are responsible for selective autophagy by tethering cargo to the site of autophagosomal engulfment. 4 In addition, it is becoming clear that post-translational modifications have an important role in ensuring substrate recognition and selectivity in vertebrates.5 For example, protein ubiquitination, besides its role in proteasome-mediated degradation, can constitute a modification that targets proteins to turnover by autophagy. 5The recognition of ubiquitinated substrates is provided by molecular adaptors including p62, NBR1, NDP52, VCP and optineurin, which bind on one side to ubiquitin and, on the other end, to autophagosome-specific proteins, such as the members of the LC3/GABARAP/Gate16 family. 4 So far, several autophagy-'specific' receptors and adaptor proteins that regulate the selective degradation of damaged organelles, protein aggregate and pathogens have been identified and partially characterized. 4,6 However, the physiological roles of selective autophagy are not yet fully understood.In this thematic issue, five reviews summarize the mechanistic and structural basis of receptor-mediated selective autophagy. Shaid et al.7 focus on the role of ubiquitinylation signals and selective autophagy receptors in selecting cargo for autophagic degradation. Suzuki 8 provides an overview of selective autophagy in yeast, concentrating on Atg11-dependent pathways. In particular, Atg11 appears to be important for organelle-selective autophagy, such as mitophagy (selective degradation of mitochondria), pexophagy (selective degradation of peroxisomes) and piecemeal microautophagy of the nucleus. In contrast, ribophagy (ribosomal degradation) could represent a non-selective and Atg-11-independent autophagic pathway.8 Ashrafi and Schwarz 9 describe the state of the art in the process of mitophagy. The selective autophagy of mitochondria is probably the only quality control mechanism that allows for eliminating these organelles upon irreversible damage. Mitophagy also mediates the removal of superfluous mitochondria from differentiating erythrocytes, and contributes to the exclusively maternal inheritance of mitochondrial DNA via the elimination of sperm-derived mitochondria.9 Liu and Czaja 10 analyse 'lipophagy', a recently identified alternat...

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“…Little is known about mammalian autophagy adaptor proteins that bind to LC3 family members and serve as an anchor point to regulate autophagosome formation around the specific cargo (Stolz et al, 2014). Similar to Atg11, ALFY (autophagy-linked FYVE protein) is a scaffolding protein implicated in aggrephagy that links cargo to the autophagic machinery (Isakson et al, 2013). Moreover, Huntingtin (HTT) has been proposed to serve as adaptor for any type of selective autophagy, because the domain of HTT shares structure similarities and binding activity with the yeast Atg11 protein and interacts with autophagic effector proteins (Ochaba et al, 2014).…”

Section: Models How Hif-2α Might Trigger Pexophagymentioning

confidence: 99%

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

2017

Frontiers Research Topics

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The role of ALFY in selective autophagy

Cited by 114 publications

References 89 publications

Identification of protein features encoded by alternative exons using Exon Ontology

Identification of protein features encoded by alternative exons using Exon Ontology

Molecular mechanisms of selective autophagy

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

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