FYCO1 Contains a C-terminally Extended, LC3A/B-preferring LC3-interacting Region (LIR) Motif Required for Efficient Maturation of Autophagosomes during Basal Autophagy

Olsvik, Hallvard Lauritz; Lamark, Trond; Takagi, Kenji; Larsen, Kenneth Bowitz; Evjen, Gry; Øvervatn, Aud; Mizushima, Tsunehiro; Johansen, Terje

doi:10.1074/jbc.m115.686915

Cited by 112 publications

(155 citation statements)

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“…Yet, induction of transport towards the cell periphery is not the only effect of FYCO1. FYCO1 was recently shown to contribute to the maturation of autophagosomes and phagophores through its LIR domain (Ma et al 2014;Olsvik et al 2015;Dionne et al 2017). Indeed, rare FYCO1 variants some of which contain missense mutations in the LIR domain have recently been associated with inclusion body myositis (G€ uttsches et al 2017) a disease characterized by accumulation of protein aggregates and suspected impaired autophagic degradation.…”

Section: Discussionmentioning

confidence: 99%

“…FYCO1 through its LC3‐interacting region (LIR) motif was shown to be important for the fusion of autophagosomes with lysosomes (Olsvik et al . ) and for the fusion of late endosomes with the plasma membrane (Raiborg et al . ).…”

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confidence: 99%

“…Accordingly, FYCO1-mCherry moved along microtubules towards the cell periphery, and over-expression of FYCO1-mCherry showed vesicular structures that were often clustered and located in the cell periphery (Pankiv et al 2010). FYCO1 through its LC3-interacting region (LIR) motif was shown to be important for the fusion of autophagosomes with lysosomes (Olsvik et al 2015) and for the fusion of late endosomes with the plasma membrane (Raiborg et al 2015).…”

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confidence: 99%

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FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

Saridaki

Nippold

Dinter

et al. 2018

Journal of Neurochemistry

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Parkinson's disease can be caused by mutations in the α-synuclein gene and is characterized by aggregates of α-synuclein protein. We have previously shown that over-expression of the small GTPase Rab7 can induce clearance of α-synuclein aggregates. In this study, we investigate which Rab7 effectors mediate this effect. To model Parkinson's disease, we expressed the pathogenic A53T mutant of α-synuclein in HEK293T cells and Drosophila melanogaster. We tested the Rab7 effectors FYVE and coiled-coil domain-containing protein 1 (FYCO1) and Rab-interacting lysosomal protein (RILP). FYCO1-EGFP-decorated vesicles containing α-synuclein. RILP-EGFP also decorated vesicular structures, but they did not contain α-synuclein. FYCO1 over-expression reduced the number of cells with α-synuclein aggregates, defined as visible particles of EGFP-tagged α-synuclein, whereas RILP did not. FYCO1 but not RILP reduced the amount of α-synuclein protein as assayed by western blot, increased the disappearance of α-synuclein aggregates in time-lapse microscopy and decreased α-synuclein-induced toxicity assayed by the Trypan blue assay. siRNA-mediated knockdown of FYCO1 but not RILP reduced Rab7-induced aggregate clearance. Collectively, these findings indicate that FYCO1 and not RILP mediates Rab7-induced aggregate clearance. The effect of FYCO1 on aggregate clearance was blocked by dominant negative Rab7 indicating that FYCO1 requires active Rab7 to function. Electron microscopic analysis and insertion of lysosomal membranes into the plasma membrane indicate that FYCO1 could lead to secretion of α-synuclein aggregates. Extracellular α-synuclein as assayed by ELISA was, however, not increased with FYCO1. Coexpression of FYCO1 in the fly model decreased α-synuclein aggregates as shown by the filter trap assay and rescued the locomotor deficit resulting from neuronal A53T-α-synuclein expression. This latter finding confirms that a pathway involving Rab7 and FYCO1 stimulates degradation of α-synuclein and could be beneficial in patients with Parkinson's disease. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

Saridaki

Nippold

Dinter

et al. 2018

Journal of Neurochemistry

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“…An alternative hypothesis is that R70 contributes to the binding of LIR domain proteins that then affect autophagosome maturation. For instance, it has recently been observed that FYCO-1, a protein required for autophagosome transport along microtubules [33] binds directly via its LIR domain to a region in LC3A and LC3B that includes R70, thereby affecting autophagosome maturation under basal conditions [34]. The precise mechanisms how a R70H substitution contributes to defective autophagosome maturation will need to be studied in further detail.…”

Section: Discussionmentioning

confidence: 99%

Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer

et al. 2016

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The cellular stress response autophagy has been implicated in various diseases including neuro-degeneration and cancer. The role of autophagy in cancer is not clearly understood and both tumour promoting and tumour suppressive effects of autophagy have been reported, which complicates the design of therapeutic strategies based on targeting the autophagy pathway. Here, we have systematically analyzed gene expression data for 47 autophagy genes for deletions, amplifications and mutations in various cancers. We found that several cancer types have frequent autophagy gene amplifications, whereas deletions are more frequent in prostate adenocarcinomas. Other cancer types such as glioblastoma and thyroid carcinoma show very few alterations in any of the 47 autophagy genes. Overall, individual autophagy core genes are altered at low frequency in cancer, suggesting that cancer cells require functional autophagy. Some autophagy genes show frequent single base mutations, such as members of the ULK family of protein kinases. Furthermore, we found hotspot mutations in the arginine-rich stretch in MAP1LC3A resulting in reduced cleavage of MAP1LC3A by ATG4B both in vitro and in vivo, suggesting a functional implication of this gene mutation in cancer development.

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“…LC3-II also contributes to cargo selection by the autophagosome which is achieved via autophagy receptors such as p62/sequestosome-1 [15, 25]. Complete autophagosomes are directed to lysosomes by the cytoskeleton [26, 27] and fusion is directed by the combined actions of Rab7a (Ras-related protein Rab-7a) GTPase, SNARE (soluble NSF [N-ethyl-maleimide-sensitive fusion protein] attachment protein receptor), and HOPS (Homotypic fusion and protein sorting) complexes [27–34]. …”

Section: Autophagy a Central Pathway In Biologymentioning

confidence: 99%

Molecular Functions of Glycoconjugates in Autophagy

Fahie

Zachara

2016

Journal of Molecular Biology

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Glycoconjugates, glycans, carbohydrates, and sugars: these terms encompass a class of biomolecules that are diverse in both form and function ranging from free oligosaccharides, glycoproteins and proteoglycans, to glycolipids that make up a complex glycan-code that impacts normal physiology and disease. Recent data suggests that one mechanism by which glycoconjugates impact physiology is through the regulation of the process of autophagy. Autophagy is a degradative pathway necessary for differentiation, organism development, and the maintenance of cell and tissue homeostasis. In this review, we will highlight what is known about the regulation of autophagy by glycoconjugates focusing on signaling mechanisms from the extracellular surface and the regulatory roles of intracellular glycans. Glycan signaling from the extracellular matrix converges on “master” regulators of autophagy including AMPK and mTORC1, thus impacting their localization, activity and/or expression. Within the intracellular milieu, gangliosides are constituents of the autophagosome membrane, a subset of proteins composing the autophagic machinery are regulated by glycosylation, and oligosaccharide exposure in the cytosol triggers an autophagic response. The examples discussed provide some mechanistic insights into glycan regulation of autophagy and reveals areas for future investigation.

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FYCO1 Contains a C-terminally Extended, LC3A/B-preferring LC3-interacting Region (LIR) Motif Required for Efficient Maturation of Autophagosomes during Basal Autophagy

Cited by 112 publications

References 47 publications

FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer

Molecular Functions of Glycoconjugates in Autophagy

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