Conserved Atg8 recognition sites mediate Atg4 association with autophagosomal membranes and Atg8 deconjugation

Abreu, Susana; Kriegenburg, Franziska; Gómez‐Sánchez, Rubén; Mari, Muriel; Sánchez, Jana; Rasmussen, Michael Schultz; Guimarães, Rodrigo Soares; Zens, Bettina; Schuschnig, Martina; Hardenberg, Ralph; Peter, Matthias; Johansen, Terje; Kraft, Claudine; Martens, Sascha; Reggiori, Fulvio

doi:10.15252/embr.201643146

Cited by 72 publications

(75 citation statements)

References 56 publications

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“…LIR2/APEAR in Figure 1), is essential for normal progression of autophagy. More precisely, the corresponding Atg4 mutant variant was not efficiently recruited to autophagosomal membranes and displayed a strong impairment in Atg8-PE deconjugation causing a decrease in autophagic flux and also a reduction in autophagosome size [2]. These data confirmed earlier findings showing that the autophagosome size is determined by the amount of available cytosolic Atg8,…”

Section: Franziska Kriegenburg and Fulvio Reggiorisupporting

confidence: 88%

“…We confirmed these data in vitro, where this mutant Atg4 variant bound to recombinant (non-lipidated) Atg8 as wild type Atg4. We thus identified a distinct region in yeast Atg4, which does not act like a classical LIR motif but rather is particularly important for the association of Atg4 with lipidated Atg8 (Atg8-PE) and hence named it APEAR (Atg8-PE association region) [2]. In our study, we also confirmed that a putative LIR sequence at the C-terminus of Atg4 (i.e.…”

Section: Editorialsupporting

confidence: 79%

“…Since the majority of proteins interact with Atg8 via the so-called LC3-interacting region (LIR) W/F/Yx-x-L/I/V [3], we scrutinized the yeast Atg4 amino acid sequence and found four potential LIR motifs (Figure 1). Our mutational analysis of these sites proved that three of them are important for Atg4 association with Atg8 in vivo [2] (i.e. pLIR1, LIR2/APEAR and LIR4 in Figure 1).…”

Section: Franziska Kriegenburg and Fulvio Reggiorimentioning

confidence: 77%

“…Our studies in yeast Saccharomyces cerevisiae revealed that Atg4 localizes transiently to autophagosomal structures and its recruitment depends on the presence of Atg8 indicating that Atg8 itself engages Atg4 at this site [2]. Since the majority of proteins interact with Atg8 via the so-called LC3-interacting region (LIR) W/F/Yx-x-L/I/V [3], we scrutinized the yeast Atg4 amino acid sequence and found four potential LIR motifs (Figure 1).…”

Section: Franziska Kriegenburg and Fulvio Reggiorimentioning

confidence: 99%

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Section: Franziska Kriegenburg and Fulvio Reggiorisupporting

confidence: 88%

Section: Editorialsupporting

confidence: 79%

Section: Franziska Kriegenburg and Fulvio Reggiorimentioning

confidence: 77%

Section: Franziska Kriegenburg and Fulvio Reggiorimentioning

confidence: 99%

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2017

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“…LC3s and GABARAPs play critical roles in facilitating the recruitment of cargo receptors and other autophagy proteins to autophagosomes by directly interacting with these proteins through conserved LC3‐interacting regions (LIRs) (Johansen & Lamark, ). After fusion with lysosomes, the fraction of LC3/GABARAP localized on the luminal side of autophagic vesicles is degraded in the lysosomes together with cargo receptors and substrates, while LC3/GABARAP present on the cytosolic face is released by Atg4 protease (Abreu et al, ).…”

Section: Introductionmentioning

confidence: 99%

The Machado–Joseph disease deubiquitylase ataxin‐3 interacts with LC3C/GABARAP and promotes autophagy

et al. 2019

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The pathology of spinocerebellar ataxia type 3, also known as Machado‐Joseph disease, is triggered by aggregation of toxic ataxin‐3 (ATXN3) variants containing expanded polyglutamine repeats. The physiological role of this deubiquitylase, however, remains largely unclear. Our recent work showed that ATX‐3, the nematode orthologue of ATXN3, together with the ubiquitin‐directed segregase CDC‐48, regulates longevity in Caenorhabditis elegans. Here, we demonstrate that the long‐lived cdc‐48.1; atx‐3 double mutant displays reduced viability under prolonged starvation conditions that can be attributed to the loss of catalytically active ATX‐3. Reducing the levels of the autophagy protein BEC‐1 sensitized worms to the effect of ATX‐3 deficiency, suggesting a role of ATX‐3 in autophagy. In support of this conclusion, the depletion of ATXN3 in human cells caused a reduction in autophagosomal degradation of proteins. Surprisingly, reduced degradation in ATXN3‐depleted cells coincided with an increase in the number of autophagosomes while levels of lipidated LC3 remained unaffected. We identified two conserved LIR domains in the catalytic Josephin domain of ATXN3 that directly interacted with the autophagy adaptors LC3C and GABARAP in vitro. While ATXN3 localized to early autophagosomes, it was not subject to lysosomal degradation, suggesting a transient regulatory interaction early in the autophagic pathway. We propose that the deubiquitylase ATX‐3/ATXN3 stimulates autophagic degradation by preventing superfluous initiation of autophagosomes, thereby promoting an efficient autophagic flux important to survive starvation.

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Hijacking intracellular membranes to feed autophagosomal growth

Staiano

Zappa

2019

FEBS Letters

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Autophagy is widely considered as a housekeeping mechanism that enables cells to survive stress conditions and, in particular, nutrient deprivation. Autophagy begins with the formation of the phagophore that expands and closes around cytosolic material and damaged organelles destined for degradation. The execution of this complex machinery is guaranteed by the coordinated action of more than 40 ATG (autophagy‐related) proteins that control the entire process at different stages from the biogenesis of the autophagosome to cargo sequestration and fusion with lysosomes. Autophagosome biogenesis occurs at multiple intracellular sites, such as the endoplasmic reticulum (ER) and the plasma membrane. Soon after the formation of the phagophore, the nascent autophagosome progressively grows in size and ultimately closes by recruiting intracellular membranes. In this review, we focus on the contribution of three membrane sources – the ER, the ER–Golgi intermediate compartment, and the Golgi complex – to autophagosome biogenesis and expansion. We also highlight the interplay between the secretory pathway and autophagy in cells when nutrients are scarce.

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Conserved Atg8 recognition sites mediate Atg4 association with autophagosomal membranes and Atg8 deconjugation

Cited by 72 publications

References 56 publications

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The Machado–Joseph disease deubiquitylase ataxin‐3 interacts with LC3C/GABARAP and promotes autophagy

Hijacking intracellular membranes to feed autophagosomal growth

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