p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy

Clausen, Terje Høyvarde; Lamark, Trond; Isakson, Pauline; Finley, Kim D.; Larsen, Kenneth Bowitz; Brech, Andreas; Øvervatn, Aud; Stenmark, Harald; Bjørkøy, Geir; Simonsen, Anne; Johansen, Terje

doi:10.4161/auto.6.3.11226

Cited by 290 publications

(302 citation statements)

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“…Similar to p62 (and NBR1), depletion of ALFY resulted in a reduced number and size of cytoplasmic p62 bodies and a diffuse localization of ubiquitinated proteins in cells treated with puromycin or the lysosomal proton pump inhibitor Bafilomycin A1. 49 However, whereas insoluble ubiquitinated proteins almost disappeared in p62 depleted cells, such proteins were still detected in ALFY depleted cells, although at a much lower level than seen in control cells. Moreover, the Drosophila p62 homolog Ref2p was shown to accumulate in ubiquitin-positive inclusions in the brains of flies carrying mutations in the ALFY homolog blue cheese (bchs), demonstrating that ALFY is required for Figure 4 (a) Model for selective autophagy of protein aggregates/p62 bodies (aggrephagy).…”

Section: Alfy and P62 In Cytoplasmic Protein Aggregate Clearancementioning

confidence: 86%

“…54,56 Interestingly, we found the PH-BEACH domains of ALFY to interact with the autophagy receptor p62. 49 Hence, the C-terminal one third of ALFY contains several domains that together have the ability to connect cargo to the autophagic machinery; a p62-binding PH-BEACH domain, an Atg5-binding WD40 domain and a FYVE domain binding to PI3P (Figure 2). Depletion of ALFY prevented efficient recruitment of Atg5, as well as LC3, to protein inclusions formed by expression of huntingtin (Htt)-polyQ, suggesting that ALFY might aid the stability of the interaction between LC3 and p62 or itself interact with LC3.…”

Section: Adaptor Proteinsmentioning

confidence: 99%

“…Supporting this model is the fact that degradation of ALFY by autophagy depends on p62, whereas p62 is turned over by autophagy independent of ubiquitinated proteins and ALFY. 49 This might reflect the need for a tight control of the level of p62 as discussed below.…”

Section: Alfy and P62 In Cytoplasmic Protein Aggregate Clearancementioning

confidence: 99%

“…48,66 PML-NBs has been associated with a broad specter of nuclear processes such as transcription, DNA repair, stress, proteolysis and apoptosis. [67][68][69] Both p62 and ALFY were found to be required for recruitment of ubiquitinated proteins to these nuclear bodies, 49 although it cannot be excluded that they rather facilitate recruitment of E3 ligases to PML-NBs for ubiquitination of misfolded proteins. p62 has been suggested to facilitate proteasome recruitment to these sites and thereby help the degradation of misfolded nuclear proteins.…”

Section: Alfy and P62 In The Nucleusmentioning

confidence: 99%

“…66 The localization of ALFY to PML-NBs is dependent on p62 and vice versa. 49 If and how nuclear aggregates are degraded by autophagy is currently not known, but three different models can be proposed; (i) p62 and ALFY bind and export misfolded ubiquitinated proteins through the nuclear pores, (ii) p62 and ALFY associate to nuclear aggregates that become degraded by autophagy during mitosis when the nuclear membrane breaks down and (iii) p62 and ALFY facilitate sorting of nuclear aggregates into nuclear membrane blebs, which become pinched off and degraded by autophagy in a process similar to yeast piecemeal microautophagy of the nucleus. 70 The finding that the nuclear oncoprotein PML/RARA, expressed in acute promyelocytic leukemia (APL) patients from a chromosomal t(15,17) translocation, is degraded by autophagy in a p62-dependent manner strongly indicate that nuclear aggregate-prone proteins can be targeted by selective autophagy.…”

Section: Alfy and P62 In The Nucleusmentioning

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: Alfy and P62 In Cytoplasmic Protein Aggregate Clearancementioning

confidence: 86%

Section: Adaptor Proteinsmentioning

confidence: 99%

Section: Alfy and P62 In Cytoplasmic Protein Aggregate Clearancementioning

confidence: 99%

Section: Alfy and P62 In The Nucleusmentioning

confidence: 99%

Section: Alfy and P62 In The Nucleusmentioning

confidence: 99%

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The role of ALFY in selective autophagy

2012

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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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Targeted Protein Degradation: Principles, Strategies, and Applications

Wen

Yang

et al. 2023

Advanced Biology

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Protein degradation is a general process to maintain cell homeostasis. The intracellular protein quality control system mainly includes the ubiquitin‐proteasome system and the lysosome pathway. Inspired by the physiological process, strategies to degrade specific proteins have developed, which emerge as potent and effective tools in biological research and drug discovery. This review focuses on recent advances in targeted protein degradation techniques, summarizing the principles, advantages, and challenges. Moreover, the potential applications and future direction in biological science and clinics are also discussed.

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p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy

Cited by 290 publications

References 48 publications

The role of ALFY in selective autophagy

The role of ALFY in selective autophagy

Phosphoinositide‐binding proteins in autophagy

Targeted Protein Degradation: Principles, Strategies, and Applications

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