Editorial

4 pages, 207 KiB

Open AccessEditorial

by Qiuhong Xiong and Ludwig Eichinger

Cells 2023, 12(18), 2212; https://doi.org/10.3390/cells12182212 - 05 Sep 2023

Viewed by 858

Autophagy is the major lysosomal pathway for the clearance of proteins, organelles and microbes in eukaryotic cells. Therefore, autophagic dysfunction can lead to numerous human diseases, like cancer or neurodegeneration, and may facilitate infections by pathogens. However, despite tremendous advances in the understanding [...] Read more.

Autophagy is the major lysosomal pathway for the clearance of proteins, organelles and microbes in eukaryotic cells. Therefore, autophagic dysfunction can lead to numerous human diseases, like cancer or neurodegeneration, and may facilitate infections by pathogens. However, despite tremendous advances in the understanding of autophagy over the past decades, the functions and regulations of autophagy-related proteins in canonical and non-canonical autophagy are still not fully resolved. The Special Issue “Model Organisms to Study Autophagy” organized by Cells includes six original articles and one review that show the latest achievements in autophagy research using different model organisms. The Special Issue summarizes and discusses different aspects of autophagy that open new avenues in understanding autophagy functions and mechanisms. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

Research

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17 pages, 2107 KiB

Open AccessArticle

Proteasomes of Autophagy-Deficient Cells Exhibit Alterations in Regulatory Proteins and a Marked Reduction in Activity

by Qiuhong Xiong, Rong Feng, Sarah Fischer, Malte Karow, Maria Stumpf, Susanne Meßling, Leonie Nitz, Stefan Müller, Christoph S. Clemen, Ning Song, Ping Li, Changxin Wu and Ludwig Eichinger

Cells 2023, 12(11), 1514; https://doi.org/10.3390/cells12111514 - 30 May 2023

Cited by 1 | Viewed by 1169

Abstract

Autophagy and the ubiquitin proteasome system are the two major processes for the clearance and recycling of proteins and organelles in eukaryotic cells. Evidence is accumulating that there is extensive crosstalk between the two pathways, but the underlying mechanisms are still unclear. We [...] Read more.

Autophagy and the ubiquitin proteasome system are the two major processes for the clearance and recycling of proteins and organelles in eukaryotic cells. Evidence is accumulating that there is extensive crosstalk between the two pathways, but the underlying mechanisms are still unclear. We previously found that autophagy 9 (ATG9) and 16 (ATG16) proteins are crucial for full proteasomal activity in the unicellular amoeba Dictyostelium discoideum. In comparison to AX2 wild-type cells, ATG9⁻and ATG16⁻ cells displayed a 60%, and ATG9⁻/16⁻ cells a 90%, decrease in proteasomal activity. Mutant cells also showed a significant increase in poly-ubiquitinated proteins and contained large ubiquitin-positive protein aggregates. Here, we focus on possible reasons for these results. Reanalysis of published tandem mass tag-based quantitative proteomic results of AX2, ATG9⁻, ATG16⁻, and ATG9⁻/16⁻ cells revealed no change in the abundance of proteasomal subunits. To identify possible differences in proteasome-associated proteins, we generated AX2 wild-type and ATG16⁻ cells expressing the 20S proteasomal subunit PSMA4 as GFP-tagged fusion protein, and performed co-immunoprecipitation experiments followed by mass spectrometric analysis. The results revealed no significant differences in the abundance of proteasomes between the two strains. However, we found enrichment as well as depletion of proteasomal regulators and differences in the ubiquitination of associated proteins for ATG16⁻, as compared to AX2 cells. Recently, proteaphagy has been described as a means to replace non-functional proteasomes. We propose that autophagy-deficient D. discoideum mutants suffer from inefficient proteaphagy, which results in the accumulation of modified, less-active, and also of inactive, proteasomes. As a consequence, these cells exhibit a dramatic decrease in proteasomal activity and deranged protein homeostasis. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

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20 pages, 6679 KiB

Open AccessArticle

Early Alterations of RNA Binding Protein (RBP) Homeostasis and ER Stress-Mediated Autophagy Contributes to Progressive Retinal Degeneration in the rd10 Mouse Model of Retinitis Pigmentosa (RP)

by Alfred Yamoah, Priyanka Tripathi, Haihong Guo, Leonie Scheve, Peter Walter, Sandra Johnen, Frank Müller, Joachim Weis and Anand Goswami

Cells 2023, 12(7), 1094; https://doi.org/10.3390/cells12071094 - 06 Apr 2023

Cited by 5 | Viewed by 1981

Abstract

The retinal degeneration 10 (rd10) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated Pde6b gene is [...] Read more.

The retinal degeneration 10 (rd10) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated Pde6b gene is selectively expressed in rod photoreceptors. We hypothesized that RNA binding protein (RBP) aggregation and abnormal autophagy might serve as early pathogenic events, damaging non-photoreceptor retinal cell types that are not primarily targeted by the Pde6b gene defect. We used a combination of immunohistochemistry (DAB, immunofluorescence), electron microscopy (EM), subcellular fractionation, and Western blot analysis on the retinal preparations obtained from both rd10 and wild-type mice. We found early, robust increases in levels of the protective endoplasmic reticulum (ER) calcium (Ca²⁺) buffering chaperone Sigma receptor 1 (SigR1) together with other ER-Ca²⁺ buffering proteins in both photoreceptors and non-photoreceptor neuronal cells before any noticeable photoreceptor degeneration. In line with this, we found markedly altered expression of the autophagy proteins p62 and LC3, together with abnormal ER widening and large autophagic vacuoles as detected by EM. Interestingly, these changes were accompanied by early, prominent cytoplasmic and nuclear aggregation of the key RBPs including pTDP-43 and FET family RBPs and stress granule formation. We conclude that progressive neurodegeneration in the rd10 mouse retina is associated with early disturbances of proteostasis and autophagy, along with abnormal cytoplasmic RBP aggregation. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

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20 pages, 17251 KiB

Open AccessArticle

mTOR-Dependent Autophagy Regulates Slit Diaphragm Density in Podocyte-like Drosophila Nephrocytes

by Dominik Spitz, Maria Comas, Lea Gerstner, Séverine Kayser, Martin Helmstädter, Gerd Walz and Tobias Hermle

Cells 2022, 11(13), 2103; https://doi.org/10.3390/cells11132103 - 02 Jul 2022

Cited by 7 | Viewed by 3113

Abstract

Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains poorly understood. We used Drosophila nephrocytes as an established [...] Read more.

Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains poorly understood. We used Drosophila nephrocytes as an established podocyte model and found that inhibition of mTOR signaling resulted in increased spacing between slit diaphragms. Gain-of-function of mTOR signaling did not affect spacing, suggesting that additional cues limit the maximal slit diaphragm density. Interestingly, both activation and inhibition of mTOR signaling led to decreased nephrocyte function, indicating that a fine balance of signaling activity is needed for proper function. Furthermore, mTOR positively controlled cell size, survival, and the extent of the subcortical actin network. We also showed that basal autophagy in nephrocytes is required for survival and limits the expression of the sns (nephrin) but does not directly affect slit diaphragm formation or endocytic activity. However, using a genetic rescue approach, we demonstrated that excessive, mTOR-dependent autophagy is primarily responsible for slit diaphragm misspacing. In conclusion, we established this invertebrate podocyte model for mechanistic studies on the role of mTOR signaling and autophagy, and we discovered a direct mTOR/autophagy-dependent regulation of the slit diaphragm architecture. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

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23 pages, 7130 KiB

Open AccessArticle

Lifespan Increase of Podospora anserina by Oleic Acid Is Linked to Alterations in Energy Metabolism, Membrane Trafficking and Autophagy

by Lea Schürmanns, Andrea Hamann and Heinz D. Osiewacz

Cells 2022, 11(3), 519; https://doi.org/10.3390/cells11030519 - 02 Feb 2022

Cited by 5 | Viewed by 2061

Abstract

The maintenance of cellular homeostasis over time is essential to avoid the degeneration of biological systems leading to aging and disease. Several interconnected pathways are active in this kind of quality control. One of them is autophagy, the vacuolar degradation of cellular components. [...] Read more.

The maintenance of cellular homeostasis over time is essential to avoid the degeneration of biological systems leading to aging and disease. Several interconnected pathways are active in this kind of quality control. One of them is autophagy, the vacuolar degradation of cellular components. The absence of the sorting nexin PaATG24 (SNX4 in other organisms) has been demonstrated to result in impairments in different types of autophagy and lead to a shortened lifespan. In addition, the growth rate and the size of vacuoles are strongly reduced. Here, we report how an oleic acid diet leads to longevity of the wild type and a PaAtg24 deletion mutant (ΔPaAtg24). The lifespan extension is linked to altered membrane trafficking, which abrogates the observed autophagy defects in ΔPaAtg24 by restoring vacuole size and the proper localization of SNARE protein PaSNC1. In addition, an oleic acid diet leads to an altered use of the mitochondrial respiratory chain: complex I and II are bypassed, leading to reduced reactive oxygen species (ROS) production. Overall, our study uncovers multiple effects of an oleic acid diet, which extends the lifespan of P. anserina and provides perspectives to explain the positive nutritional effects on human aging. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

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13 pages, 4008 KiB

Open AccessArticle

Komagataella phaffii Cue5 Piggybacks on Lipid Droplets for Its Vacuolar Degradation during Stationary Phase Lipophagy

by Ravinder Kumar, Ankit Shroff and Taras Y. Nazarko

Cells 2022, 11(2), 215; https://doi.org/10.3390/cells11020215 - 10 Jan 2022

Cited by 8 | Viewed by 3380

Abstract

Recently, we developed Komagataella phaffii (formerly Pichia pastoris) as a model for lipophagy, the selective autophagy of lipid droplets (LDs). We found that lipophagy pathways induced by acute nitrogen (N) starvation and in stationary (S) phase have different molecular mechanisms. Moreover, both [...] Read more.

Recently, we developed Komagataella phaffii (formerly Pichia pastoris) as a model for lipophagy, the selective autophagy of lipid droplets (LDs). We found that lipophagy pathways induced by acute nitrogen (N) starvation and in stationary (S) phase have different molecular mechanisms. Moreover, both types of lipophagy are independent of Atg11, the scaffold protein that interacts with most autophagic receptors and, therefore, is essential for most types of selective autophagy in yeast. Since yeast aggrephagy, the selective autophagy of ubiquitinated protein aggregates, is also independent of Atg11 and utilizes the ubiquitin-binding receptor, Cue5, we studied the relationship of K. phaffii Cue5 with differentially induced LDs and lipophagy. While there was no relationship of Cue5 with LDs and lipophagy under N-starvation conditions, Cue5 accumulated on LDs in S-phase and degraded together with LDs via S-phase lipophagy. The accumulation of Cue5 on LDs and its degradation by S-phase lipophagy strongly depended on the ubiquitin-binding CUE domain and Prl1, the positive regulator of lipophagy 1. However, unlike Prl1, which is required for S-phase lipophagy, Cue5 was dispensable for it suggesting that Cue5 is rather a new substrate of this pathway. We propose that a similar mechanism (Prl1-dependent accumulation on LDs) might be employed by Prl1 to recruit another ubiquitin-binding protein that is essential for S-phase lipophagy. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

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16 pages, 5205 KiB

Open AccessArticle

Atg5 Regulates Selective Autophagy of the Parental Macronucleus during Tetrahymena Sexual Reproduction

by Tao Bo, Yu Kang, Ya Liu, Jing Xu and Wei Wang

Cells 2021, 10(11), 3071; https://doi.org/10.3390/cells10113071 - 08 Nov 2021

Cited by 4 | Viewed by 1883

Abstract

Nuclear autophagy is an important selective autophagy process. The selective autophagy of sexual development micronuclei (MICs) and the programmed nuclear degradation of parental macronucleus (paMAC) occur during sexual reproduction in Tetrahymena thermophila. The molecular regulatory mechanism of nuclear selective autophagy is unclear. [...] Read more.

Nuclear autophagy is an important selective autophagy process. The selective autophagy of sexual development micronuclei (MICs) and the programmed nuclear degradation of parental macronucleus (paMAC) occur during sexual reproduction in Tetrahymena thermophila. The molecular regulatory mechanism of nuclear selective autophagy is unclear. In this study, the autophagy-related protein Atg5 was identified from T. thermophila. Atg5 was localized in the cytoplasm in the early sexual-development stage and was localized in the paMAC in the late sexual-development stage. During this stage, the degradation of meiotic products of MIC was delayed in atg5i mutants. Furthermore, paMAC was abnormally enlarged and delayed or failed to degrade. The expression level and lipidation of Atg8.2 significantly decreased in the mutants. All these results indicated that Atg5 was involved in the regulation of the selective autophagy of paMAC by regulating Atg8.2 in Tetrahymena. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

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Review

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23 pages, 2049 KiB

Open AccessReview

The Interplay between Autophagy and Virus Pathogenesis—The Significance of Autophagy in Viral Hepatitis and Viral Hemorrhagic Fevers

by Dominika Bębnowska and Paulina Niedźwiedzka-Rystwej

Cells 2022, 11(5), 871; https://doi.org/10.3390/cells11050871 - 03 Mar 2022

Cited by 7 | Viewed by 2783

Abstract

Autophagy is a process focused on maintaining the homeostasis of organisms; nevertheless, the role of this process has also been widely documented in viral infections. Thus, xenophagy is a selective form of autophagy targeting viruses. However, the relation between autophagy and viruses is [...] Read more.

Autophagy is a process focused on maintaining the homeostasis of organisms; nevertheless, the role of this process has also been widely documented in viral infections. Thus, xenophagy is a selective form of autophagy targeting viruses. However, the relation between autophagy and viruses is ambiguous—this process may be used as a strategy to fight with a virus, but is also in favor of the virus’s replication. In this paper, we have gathered data on autophagy in viral hepatitis and viral hemorrhagic fevers and the relations impacting its viral pathogenesis. Thus, autophagy is a potential therapeutic target, but research is needed to fully understand the mechanisms by which the virus interacts with the autophagic machinery. These studies must be performed in specific research models other than the natural host for many reasons. In this paper, we also indicate Lagovirus europaeus virus as a potentially good research model for acute liver failure and viral hemorrhagic disease. Full article

(This article belongs to the Special Issue Model Organisms to Study Autophagy)

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