Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes

Simonsen, Anne; Birkeland, Hanne C.G.; Gillooly, David J.; Mizushima, Noboru; Kuma, Akiko; Yoshimori, Tamotsu; Slagsvold, Thomas; Brech, Andreas; Stenmark, Harald

doi:10.1242/jcs.01287

Cited by 261 publications

(320 citation statements)

References 44 publications

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“…ALFY interacts directly with the autophagy receptor p62 and with the core autophagy protein Atg5, as well as with phosphatidylinositol 3-phosphate (PI3P) found in autophagic membranes, suggesting that it functions as a scaffolding protein. 47 (Figure 2, indicated as regions of interest I, II and III). Most notable of these is region I (residues 247-351 of ALFY) that is similar to a large part of the TBC domain of 'TBC1 domain family member 30'.…”

Section: Adaptor Proteinsmentioning

confidence: 99%

“…ALFY rather colocalizes with ubiquitin-and p62-positive protein aggregates and to a certain degree with autophagic membranes. 47 Recruitment of ALFY to protein aggregates seems not to depend on its binding to PI3P. 47 However, as the class III PI3K/Vps34 complex, and by extension PI3P, is required for aggrephagy, ALFY may be involved in recruting PI3P-containing autophagic membranes to protein aggregates.…”

Section: Adaptor Proteinsmentioning

confidence: 99%

“…14,65 Under normal conditions ALFY is predominantly localized to the nucleus and undergoes continuous nucleocytoplasmic shuttling. 47 Upon cellular stress leading to protein aggregate formation ALFY relocates from the nucleus to cytoplasmic p62 bodies ( Figure 4). It is not known what signals ALFY nuclear export upon protein aggregate formation, but p62 might be involved as discussed below.…”

Section: Alfy and P62 In Cytoplasmic Protein Aggregate Clearancementioning

confidence: 99%

“…The core Atg machinery is required for both non-selective and selective autophagy and a competition between these two types of autophagy for the same molecular machinery could be detrimental for cells undergoing starvation. Tissue expression levels of ALFY (highest in the brain and lowest in the liver) 47 inversely correlate with responsiveness to starvation and suggest that ALFY may be especially important in neurons, non-dividing cells in which removal of toxic aggregation-prone proteins is essential for survival. Thus, regulation of the ALFY level or localization might be a way for the cell to regulate starvationinduced autophagy versus aggrephagy.…”

Section: Alfy and Regulation Of Selective Autophagymentioning

confidence: 99%

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The role of ALFY in selective autophagy

2012

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Autophagy, a highly conserved lysosomal degradation pathway, was initially characterized as a bulk degradation system induced in response to starvation. In recent years, autophagy has emerged also as a highly selective pathway, targeting various cargoes such as aggregated proteins and damaged organelles for degradation. The key factors involved in selective autophagy are autophagy receptors and adaptor proteins, which connect the cargo to the core autophagy machinery. In this review, we discuss the current knowledge about the only mammalian adaptor protein identified thus far, autophagy-linked FYVE protein (ALFY). ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. We also comment on the possible role of ALFY in the context of disease.

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Section: Adaptor Proteinsmentioning

confidence: 99%

Section: Adaptor Proteinsmentioning

confidence: 99%

Section: Alfy and P62 In Cytoplasmic Protein Aggregate Clearancementioning

confidence: 99%

Section: Alfy and Regulation Of Selective Autophagymentioning

confidence: 99%

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The role of ALFY in selective autophagy

2012

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“…Several of the genes identified in this study encoded proteins previously linked to autophagy. These included proteins involved in autophagosome formation (Sato and Nakano, 2007), the fusion of autophagosomes with the vacuole (Ishihara et al, 2001), as well as proteins that regulate autophagy (Meijer and Codogno, 2004;Simonsen et al, 2004). It is thus possible that autophagy is triggered during vegetative incompatibility in A. areolatum to clear degraded DNA and proteins, damaged organelles, etc.…”

Section: Discussionmentioning

confidence: 99%

Gene expression associated with vegetative incompatibility in Amylostereum areolatum

Nest¹,

Steenkamp²,

Slippers³

et al. 2011

Fungal Genetics and Biology

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In filamentous fungi, vegetative compatibility among individuals of the same species is determined by the genes encoded at the heterokaryon incompatibility (het) loci. The hyphae of genetically similar individuals that share the same allelic specificities at their het loci are able to fuse and intermingle, while different allelic specificities at the het loci result in cell death of the interacting hyphae. In this study, suppression subtractive hybridization (SSH) followed by pyrosequencing and quantitative reverse transcription PCR were used to identify genes that are selectively expressed when vegetatively incompatible individuals of Amylostereum areolatum interact. The SSH library contained genes associated with various cellular processes, including cell-cell adhesion, stress and defence responses, as well as cell death. Some of the transcripts encoded proteins that were previously implicated in the stress and defence responses associated with vegetative incompatibility. Other transcripts encoded proteins known to be associated with programmed cell death, but have not previously been linked with vegetative incompatibility.Results of this study have considerably increased our knowledge of the processes underlying vegetative incompatibility in Basidiomycetes in general and A. areolatum in particular.

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Phosphoinositide‐binding proteins in autophagy

Lystad

Simonsen

2016

FEBS Letters

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Edited by Wilhelm JustPhosphoinositides represent a very small fraction of membrane phospholipids, having fast turnover rates and unique subcellular distributions, which make them perfect for initiating local temporal effects. Seven different phosphoinositide species are generated through reversible phosphorylation of the inositol ring of phosphatidylinositol (PtdIns). The negative charge generated by the phosphates provides specificity for interaction with various protein domains that commonly contain a cluster of basic residues. Examples of domains that bind phosphoinositides include PH domains, WD40 repeats, PX domains, and FYVE domains. Such domains often display specificity toward a certain species or subset of phosphoinositides. Here we will review the current literature of different phosphoinositide-binding proteins involved in autophagy.Keywords: autophagy; FYVE; PH; phosphoinositide; PX AutophagyAutophagy is the process by which cellular components are transported to the lysosome (or the yeast vacuole) for degradation to provide cellular homeostasis and quality control. There are three main forms of autophagy, namely microautophagy, which involves a direct engulfment of cytosolic cargo by the endosomal or lysosomal/vacuolar membrane, chaperone-mediated autophagy (CMA), involving lysosomal translocation of cytosolic protein cargo, and macroautophagy, a vesicle transport pathway where cargo is sequestered into double-membrane autophagosomes which undergo fusion with endosomes and/or the lysosome/vacuole. Autophagy is induced upon cellular stress (e.g., starvation) to facilitate cell survival by providing building blocks that can be used to produce essential molecules and generate energy. However, autophagy also serves an important quality control function under basal conditions by selective clearance of damaged or dysfunctional cellular components [1].Macroautophagy (hereafter autophagy) involves nucleation of a phagophore membrane (also called the isolation membrane) from specific phosphatidyl inositol 3-phosphate (PtdIns3P)-enriched structures, called the phagophore assembly site (PAS, a peri-vacuolar structure) in yeast and the omegasome (associated with the endoplasmic reticulum, ER) in mammals. Typically, there is only a single PAS in yeast, while several ER-associated omegasomes are detected upon Abbreviations ALFY, autophagy-linked FYVE protein; Arf6, adenosine diphosphate ribosylation factor 6; ATG, autophagy-related; BATS, biotin and thiamin synthesis-associated domain; Cvt, cytoplasm-to-vacuole; DFCP1, double FYVE-containing protein 1; ER, endoplasmic reticulum; FYCO1, FYVE and coiled-coil domain-containing 1; GRAM, glycosyltransferases Rab-like GTPase activators and myotubularins; HOPS, homotypic fusion and protein sorting; Hsv2, homologous with swollen vacuole phenotype 2; LIR, LC3-interacting region; MTMR3, myotubularin-related protein 3; mTORC1, mechanistic target of rapamycin complex 1; PA, phosphatidic acid; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide-dependent protein kinase ...

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Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes

Cited by 261 publications

References 44 publications

The role of ALFY in selective autophagy

The role of ALFY in selective autophagy

Gene expression associated with vegetative incompatibility in Amylostereum areolatum

Phosphoinositide‐binding proteins in autophagy

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