Super-assembly of ER-phagy receptor Atg40 induces local ER remodeling at contacts with forming autophagosomal membranes

Mochida, Keisuke; Yamasaki, Akinori; Matoba, Kazuaki; Kirisako, Hiromi; Noda, Nobuo N.; Nakatogawa, Hitoshi

doi:10.1038/s41467-020-17163-y

Cited by 58 publications

(71 citation statements)

References 53 publications

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“…To fragment ER membrane and load into the autophagosome, multiple membrane-resident Atg40 proteins simultaneously engage a number of Atg8 proteins, which they bind with their AIMs tightly, owing to the short helix C-terminal to AIMs. Importantly, this feature is conserved all the way to the mammalian ERphagy-specific SARs [110]. Increase in the affinity in some cases can reach >1000 fold.…”

Section: Extended Lir Motifs: C-terminal α-Helical Extensionsmentioning

confidence: 90%

Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

Wesch

Kirkin

Rogov

2020

Cells

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Autophagy is a common name for a number of catabolic processes, which keep the cellular homeostasis by removing damaged and dysfunctional intracellular components. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. A central axis of autophagy is formed along the interactions of autophagy modifiers (Atg8-family proteins) with a variety of their cellular counter partners. Besides autophagy, Atg8-proteins participate in many other pathways, among which membrane trafficking and neuronal signaling are the most known. Despite the fact that autophagy modifiers are well-studied, as the small globular proteins show similarity to ubiquitin on a structural level, the mechanism of their interactions are still not completely understood. A thorough analysis and classification of all known mechanisms of Atg8-protein interactions could shed light on their functioning and connect the pathways involving Atg8-proteins. In this review, we present our views of the key features of the Atg8-proteins and describe the basic principles of their recognition and binding by interaction partners. We discuss affinity and selectivity of their interactions as well as provide perspectives for discovery of new Atg8-interacting proteins and therapeutic approaches to tackle major human diseases.

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Section: Extended Lir Motifs: C-terminal α-Helical Extensionsmentioning

confidence: 90%

Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

Wesch

Kirkin

Rogov

2020

Cells

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“…Key unknowns to unraveling the nucleophagy mechanism are determining whether Atg39 acts from the ONM or the INM (or both), and whether, like other cargo adaptors 34–36 it has any inherent membrane remodeling activity. To address the former, we took advantage of a recently developed split-GFP reporter system used to catalogue the INM proteome 37 .…”

Section: Resultsmentioning

confidence: 99%

Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome

Chandra

Mannino

Thaller

et al. 2021

Preprint

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Mechanisms that turnover components of the nucleus and inner nuclear membrane (INM) remain to be fully defined. We explore how components of the INM are selected by a cytosolic autophagy apparatus through a transmembrane nuclear envelope-localized cargo adaptor, Atg39. A split-GFP reporter shows that Atg39 localizes to the outer nuclear membrane (ONM) and thus targets the INM across the nuclear envelope lumen. Consistent with this, sequence elements that confer both nuclear envelope localization and a membrane remodeling activity are mapped to the Atg39 lumenal domain; these lumenal motifs are required for the autophagy-mediated degradation of an integral INM protein. Interestingly, correlative light and electron tomography shows that the overexpression of Atg39 leads to the expansion of the ONM and the enclosure of a network of INM-derived vesicles in the nuclear envelope lumen. Thus, we propose an outside-in model of nucleophagy where INM is delivered into vesicles in the nuclear envelope lumen, which can be targeted by the autophagosome.

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“…Yeast cells were analyzed using two different fluorescence microscopy systems, as described previously (Mochida et al, 2020). The images in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Atg39-mCherry puncta and mNG-Atg8 puncta were detected using the Find Maxima function of Fiji as described previously (Mochida et al, 2020). When the maxima of Atg39-mCherry puncta exists within 272 nm of those of GFP- or mNG-Atg8 puncta, they were classified as GFP/mNG-Atg8-positive.…”

Section: Methodsmentioning

confidence: 99%

Atg39 links and deforms the outer and inner nuclear membranes in selective autophagy of the nucleus

Mochida

Otani

Katsumata

et al. 2021

Preprint

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In selective autophagy of the nucleus (hereafter nucleophagy), nucleus-derived double membrane vesicles (NDVs) are formed, sequestered within autophagosomes, and delivered to lysosomes or vacuoles for degradation. In Saccharomyces cerevisiae, the nuclear envelope (NE) protein Atg39 acts as a nucleophagy receptor, which interacts with Atg8 to target NDVs to forming autophagosomal membranes. In this study, we revealed that Atg39 is anchored to the outer nuclear membrane (ONM) via its transmembrane domain and also associated with the inner nuclear membrane (INM) via membrane-binding amphipathic helices (APHs) in its perinuclear space region, thereby linking these membranes. We also revealed that overaccumulation of Atg39 causes the NE to protrude towards the cytoplasm, and the tips of the protrusions are pinched off to generate NDVs. The APHs of Atg39 are crucial for Atg39 assembly in the NE and subsequent NE protrusion. These findings suggest that the nucleophagy receptor Atg39 plays pivotal roles in NE deformation during the generation of NDVs to be degraded by nucleophagy.

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Super-assembly of ER-phagy receptor Atg40 induces local ER remodeling at contacts with forming autophagosomal membranes

Cited by 58 publications

References 53 publications

Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome

Atg39 links and deforms the outer and inner nuclear membranes in selective autophagy of the nucleus

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