Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus

Abstract Autophagy is a process in which a myriad membrane structures called autophagosomes are formed de novo in a single cell, which deliver the engulfed substrates into lysosomes for degradation. The size of the autophagosomes is relatively uniform in non-selective autophagy and variable in selective autophagy. It has been recently established that autophagosome formation occurs near the endoplasmic reticulum (ER). In this review, we have discussed recent advances in the relationship between autophagosome formation and endoplasmic reticulum. Autophagosome formation occurs near the ER subdomain enriched with phospholipid synthesizing enzymes like phosphatidylinositol synthase (PIS)/CDP-diacylglycerol-inositol 3-phosphatidyltransferase (CDIPT) and choline/ethanolamine phosphotransferase 1 (CEPT1). Autophagy-related protein 2 (Atg2), which is involved in autophagosome formation has a lipid transfer capacity and is proposed to directly transfer the lipid molecules from the ER to form autophagosomes. Vacuole membrane protein 1 (VMP1) and transmembrane protein 41b (TMEM41b) are ER membrane proteins that are associated with the formation of the subdomain. Recently, we have reported that an uncharacterized ER membrane protein possessing the DNAJ domain, called ERdj8/DNAJC16, is associated with the regulation of the size of autophagosomes. The localization of ERdj8/DNAJC16 partially overlaps with the PIS-enriched ER subdomain, thereby implying its association with autophagosome size determination.

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Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform

Developmental Cell ◽

10.1016/j.devcel.2019.06.016 ◽

2019 ◽

Vol 50 (5) ◽

pp. 627-643.e5 ◽

Cited By ~ 24

Author(s):

Maria Zachari ◽

Sigurdur R. Gudmundsson ◽

Ziyue Li ◽

Maria Manifava ◽

Fiorella Cugliandolo ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Selective Autophagy

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Atlastins mediate selective autophagy of the endoplasmic reticulum

10.1101/274530 ◽

2018 ◽

Cited By ~ 1

Author(s):

Jin Rui Liang ◽

Emily Lingeman ◽

Saba Ahmed ◽

Jacob Corn

Keyword(s):

Flow Cytometry ◽

Endoplasmic Reticulum ◽

Spastic Paraplegia ◽

Lysosomal Degradation ◽

Gtpase Domain ◽

Selective Autophagy ◽

Membrane Morphology ◽

Degenerative Disorders ◽

Starvation Conditions ◽

Er Membrane

ABSTRACTThe selective lysosomal degradation (autophagy) of entire organelles is required for cellular homeostasis, and its dysregulation is involved in degenerative disorders such as Parkinson’s Disease. While autophagy of mitochondria (mitophagy) is becoming better understood, other forms of organelle autophagy are relatively unexplored. Here we develope multiple quantitative assays to measure organelle autophagy using flow cytometry, microscopy, and Western blotting. Focusing on autophagy of the endoplasmic reticulum (ER-phagy), we show that these assays allow facile measurement of ER-phagy, and that ER-phagy is inhibited by knockdown of either core autophagy components or the recently reported FAM134B ER-phagy receptor. Using these assays, we further identify that Atlastins, the ER-resident GTPases involved in ER membrane morphology, are key positive effectors of ER-phagy. Atlastin-depleted cells have decreased ER-phagy under starvation conditions, and Atlastin’s role in ER-phagy requires both a functional GTPase domain and proper ER localization. The three Atlastin family members functionally compensate for one another during ER-phagy and may form heteromeric complexes with one another. We also find that Atlastins act downstream of the FAM134B ER-phagy receptor. We propose that during ER-phagy, Atlastins remodel ER membrane to separate pieces of FAM134B-marked ER for efficient autophagosomal engulfment. Human mutations in Atlastins led to hereditary spastic paraplegia, and our results suggest that this disease may be linked to deficiencies in ER-phagy rather than ER morphology.

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ESCRT machinery mediates selective microautophagy of endoplasmic reticulum

10.1101/661306 ◽

2019 ◽

Author(s):

Jasmin A. Schäfer ◽

Julia P. Schessner ◽

Peter W. Bircham ◽

Takuma Tsuji ◽

Charlotta Funaya ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Lysosomal Membrane ◽

Misfolded Proteins ◽

Selective Autophagy ◽

Escrt Machinery ◽

Parallel Pathways ◽

Mechanistic Understanding ◽

Er Homeostasis ◽

Er Whorls

ABSTRACTER-phagy, the selective autophagy of endoplasmic reticulum (ER), safeguards organelle homeostasis by eliminating misfolded proteins and regulating ER size. ER-phagy can occur by macroautophagic and microautophagic mechanisms. While dedicated machinery for macro-ER-phagy has been discovered, the molecules and mechanisms mediating micro-ER-phagy remain unknown. Here, we first show that micro-ER-phagy in yeast involves the conversion of stacked cisternal ER into multilamellar ER whorls during microautophagic uptake into lysosomes. Second, we identify the conserved Nem1-Spo7 phosphatase complex and ESCRT proteins as key components for micro-ER-phagy. Third, we demonstrate that macro- and micro-ER-phagy are parallel pathways with distinct molecular requirements. Finally, we provide evidence that ESCRT proteins directly function in scission of the lysosomal membrane to complete the microautophagic uptake of ER. These findings establish a framework for a mechanistic understanding of micro-ER-phagy and, thus, a comprehensive appreciation of the role of autophagy in ER homeostasis.

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Author response: Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy

10.7554/elife.25555.039 ◽

2017 ◽

Cited By ~ 3

Author(s):

Paolo Grumati ◽

Giulio Morozzi ◽

Soraya Hölper ◽

Muriel Mari ◽

Marie-Lena IE Harwardt ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Full Length ◽

Author Response ◽

Selective Autophagy ◽

Tubular Endoplasmic Reticulum

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Autophagy in Neurons

Annual Review of Cell and Developmental Biology ◽

10.1146/annurev-cellbio-100818-125242 ◽

2019 ◽

Vol 35 (1) ◽

pp. 477-500 ◽

Cited By ~ 24

Author(s):

Andrea K.H. Stavoe ◽

Erika L.F. Holzbaur

Keyword(s):

Endoplasmic Reticulum ◽

Cell Biology ◽

Neuronal Development ◽

Selective Autophagy ◽

The Core ◽

Differentiated Cells ◽

Neuronal Homeostasis ◽

Core Components ◽

Cellular Organelles

Autophagy is the major cellular pathway to degrade dysfunctional organelles and protein aggregates. Autophagy is particularly important in neurons, which are terminally differentiated cells that must last the lifetime of the organism. There are both constitutive and stress-induced pathways for autophagy in neurons, which catalyze the turnover of aged or damaged mitochondria, endoplasmic reticulum, other cellular organelles, and aggregated proteins. These pathways are required in neurodevelopment as well as in the maintenance of neuronal homeostasis. Here we review the core components of the pathway for autophagosome biogenesis, as well as the cell biology of bulk and selective autophagy in neurons. Finally, we discuss the role of autophagy in neuronal development, homeostasis, and aging and the links between deficits in autophagy and neurodegeneration.

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Reconstitution of autophagosome nucleation defines Atg9 vesicles as seeds for membrane formation

Science ◽

10.1126/science.aaz7714 ◽

2020 ◽

Vol 369 (6508) ◽

pp. eaaz7714 ◽

Cited By ~ 2

Author(s):

Justyna Sawa-Makarska ◽

Verena Baumann ◽

Nicolas Coudevylle ◽

Sören von Bülow ◽

Veronika Nogellova ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

De Novo ◽

Lipid Transfer ◽

Related Protein ◽

Membrane Formation ◽

Selective Autophagy ◽

Membrane Contact Sites ◽

Contact Sites ◽

Membrane Contact ◽

Phosphatidylinositol 3

Autophagosomes form de novo in a manner that is incompletely understood. Particularly enigmatic are autophagy-related protein 9 (Atg9)–containing vesicles that are required for autophagy machinery assembly but do not supply the bulk of the autophagosomal membrane. In this study, we reconstituted autophagosome nucleation using recombinant components from yeast. We found that Atg9 proteoliposomes first recruited the phosphatidylinositol 3-phosphate kinase complex, followed by Atg21, the Atg2-Atg18 lipid transfer complex, and the E3-like Atg12–Atg5-Atg16 complex, which promoted Atg8 lipidation. Furthermore, we found that Atg2 could transfer lipids for Atg8 lipidation. In selective autophagy, these reactions could potentially be coupled to the cargo via the Atg19-Atg11-Atg9 interactions. We thus propose that Atg9 vesicles form seeds that establish membrane contact sites to initiate lipid transfer from compartments such as the endoplasmic reticulum.

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