A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage

Samaddar, Madhuja; Goudeau, Jérôme; Sanchez, Melissa; Hall, David H.; Bohnert, K. Adam; Ingaramo, Maria; Kenyon, Cynthia

doi:10.7554/elife.62653

Cited by 14 publications

(8 citation statements)

References 74 publications

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“…Microautophagy has yet to be characterized in C . elegans [ 69 ], yet, 2 recent studies provide evidence for macroautophagy-independent degradation of cytosolic cargo by the lysosome evocative of microautophagy [ 70 – 72 ]. Further work is needed to establish how SAPA would rely on microautophagy to stop the aggregation of certain globular proteins during core PQC failure.…”

Section: Discussionmentioning

confidence: 99%

A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans

Jung,

Lechler,

Fernandez-Villegas

et al. 2023

PLoS Biol

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During aging, proteostasis capacity declines and distinct proteins become unstable and can accumulate as protein aggregates inside and outside of cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of cytoplasmic protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of 3 core protein quality control systems, namely chaperones, the proteasome, and macroautophagy, leads to lower levels of age-dependent protein aggregation in Caenorhabditis elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism that selectively targets newly synthesized proteins to suppress their aggregation and associated proteotoxicity. The safety mechanism relies on macroautophagy-independent lysosomal degradation and involves several previously uncharacterized components of the intracellular pathogen response (IPR). We propose that this protective mechanism engages an anti-aggregation machinery targeting aggregating proteins for lysosomal degradation.

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Section: Discussionmentioning

confidence: 99%

A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans

Jung,

Lechler,

Fernandez-Villegas

et al. 2023

PLoS Biol

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“…The findings regarding the Lysotracker also revealed that both PIP2 and PMA significantly affected lysosome acidification in cumulus cells, but DOG did not have this effect on these cells. In one of the recent studies, Samaddar et al (2021) revealed that suppression of lysosomal V‐ATPase, vesicle‐transport or proteasome function increases the speed of age‐dependent protein aggregation in the soma and preserves proteostasis in the ageing soma which links the processes that improve proteostasis in the immortal germ lineage. Our study, proving the assistance of PIP2 and PMA in protein degradation, raised the question of whether these factors could also cause a degradation of vital proteins which take important roles for both oocytes and cumulus cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of proteolysis in bovine cumulus cells with possible inclusion of proton pump activators

Coruhlu

Tepekoy

2023

Reprod Domestic Animals

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The aim of this study was to reveal the effects of V‐ATPase proton pump activation on lysosomal acidity and protein degradation in cultured cumulus cells. Cumulus cells from bovine ovaries were cultured in the presence of 10 and 50 μM doses of V‐ATPase proton pump activators PIP2, PMA and DOG for 12 and 24 h. At the end of the culture period, the level of protein degradation was evaluated through DQ‐Red‐BSA analysis and the lysosomes were detected through a fluorescent probe. In addition, total and phosphorylated MAPK1/3 and AKT protein levels of cumulus cells were determined through Western blotting. PIP2 and PMA were shown to increase protein degradation and lysosomal acidity in cultured bovine cumulus cells, whereas DOG did not have any significant effects on these cells. Total and phosphorylated MAPK and AKT protein levels were higher in PIP2 and PMA groups compared with the control and DOG. It was concluded that particular proton pump activators can enhance protein degradation and lysosomal acidification in cultured bovine cumulus cells without having detrimental effects on cell signalling members required for cell viability and proper functioning. Due to the cellular interactions, increasing the lysosomal activity in cumulus cells in the culture environment could also affect the removal of protein aggregates in the oocytes. This strategy could be effective for improving in vitro maturation of the oocytes by providing proteostasis.

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“…It has been reported that in vesicles with presenilin-1 (PS1) deficiency, lysosomal pH deficiency leads to a significant increase in lysosomal pH, leading to dysregulation of proteolytic enzymes (J. H. Lee et al, 2010Lee et al, , 2015. In addition, deacidification and elevated intracellular pH inhibit enzyme activity in the intimal binding compartment, thus disrupting the clearance of protein aggregates (Samaddar et al, 2021;Santerre et al, 2021). In addition, elevated endonuclease and lysosome pH may have an overall effect on the proteome.…”

Section: V-atpase and Lysosome Acidificationmentioning

confidence: 99%

Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link

Guo,

Li,

Liu

et al. 2024

Eur J of Neuroscience

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Globally, the incidence of diabetes mellitus (DM) and Alzheimer's disease (AD) is increasing year by year, causing a huge economic and social burden, and their pathogenesis and aetiology have been proven to have a certain correlation. In recent years, more and more studies have shown that vacuolar adenosine triphosphatases (v‐ATPases) in eukaryotes, which are biomolecules regulating lysosomal acidification and glycolipid metabolism, play a key role in DM and AD. This article describes the role of v‐ATPase in DM and AD, including its role in glycolysis, insulin secretion and insulin resistance (IR), as well as its relationship with lysosomal acidification, autophagy and β‐amyloid (Aβ). In DM, v‐ATPase is involved in the regulation of glucose metabolism and IR. v‐ATPase is closely related to glycolysis. On the one hand, v‐ATPase affects the rate of glycolysis by affecting the secretion of insulin and changing the activities of key glycolytic enzymes hexokinase (HK) and phosphofructokinase 1 (PFK‐1). On the other hand, glucose is the main regulator of this enzyme, and the assembly and activity of v‐ATPase depend on glucose, and glucose depletion will lead to its decomposition and inactivation. In addition, v‐ATPase can also regulate free fatty acids, thereby improving IR. In AD, v‐ATPase can not only improve the abnormal brain energy metabolism by affecting lysosomal acidification and autophagy but also change the deposition of Aβ by affecting the production and degradation of Aβ. Therefore, v‐ATPase may be the bridge between DM and AD.

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A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage

Cited by 14 publications

References 74 publications

A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans

A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans

Regulation of proteolysis in bovine cumulus cells with possible inclusion of proton pump activators

Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link

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