Autophagy protein ATG-16.2 and its WD40 domain mediate the beneficial effects of inhibiting early-acting autophagy genes in C. elegans neurons

Yang, Yongzhi; Arnold, Meghan Lee; Lange, Caitlin M.; Sun, Ling-Hsuan; Broussalian, Michael; Doroodian, Saam; Ebata, Hiroshi; Choy, Elizabeth H.; Poon, Karie; Moreno, Tatiana M.; Singh, Anupama; Driscoll, Monica; Kumsta, Caroline; Hansen, Malene

doi:10.1038/s43587-023-00548-1

Cited by 7 publications

(4 citation statements)

References 70 publications

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“…S2A, Table S2 ). Since this could potentially be due to leakiness of the rab-3p compared to the rgef-1p 18,19 , in our subsequent studies, we focused on making comparisons to results from the rgef-1p::xbp-1s strain (which we will continue to refer to as neuronal xbp-1s ).…”

Section: Resultsmentioning

confidence: 99%

Distinct mechanisms of non-autonomous UPR^ERmediated by GABAergic, glutamatergic, and octopaminergic neurons

Coakley,

Hruby,

Wang

et al. 2024

Preprint

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The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRERby overexpression of the major transcription factor,xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissue to activate UPRERin a non-autonomous fashion. Previous work identified serotonergic and dopaminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRERsolely in glutamatergic, octopaminergic, and GABAergic neurons inC. elegansand paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while minor, but statistically significant changes were observed in lipid metabolism-related genes with GABAergic UPRERactivation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.

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Section: Resultsmentioning

confidence: 99%

Distinct mechanisms of non-autonomous UPR^ERmediated by GABAergic, glutamatergic, and octopaminergic neurons

Coakley,

Hruby,

Wang

et al. 2024

Preprint

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“…Intermediate filaments that associate with aggresomes are required cell-autonomously for exopher production [33] . Additionally, the autophagy protein ATG-16.2 has been found to promote exopher production cell autonomously [34] . Complementing these findings in stress-response pathways, we discovered that the apoptosis trigger in C. elegans , the BH3-only protein EGL-1, has a non-apoptotic function in promoting exopher production cell-autonomously.…”

Section: Discussionmentioning

confidence: 99%

Non-apoptotic role of EGL-1 in exopher production and neuronal health inCaenorhabditis elegans

Wu,

Cardona,

Pierce

2024

Preprint

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While traditionally studied for their pro-apoptotic functions, recent research suggests BH3-only proteins also have non-apoptotic roles. Here, we find that EGL-1, the BH3-only protein inCaenorhabditis elegans, promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the mechanistic role of BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health.Significance statementBH3-only proteins were known for their function in inducing cell death. Their presence in healthy adult neurons, however, suggests additional roles. Our study focused on the BH3-only protein EGL-1 in the nematodeCaenorhabditis elegans, where its apoptotic role was discovered. We reveal a new role in cell-autonomously promoting exopher production – a process where neurons extrude large vesicles containing potentially harmful cell contents. EGL-1 appears to promote this by regulating mitochondrial dynamics. We also report that low levels of EGL-1 benefit neuronal health and function. These findings expand our understanding of BH3-only proteins, mitochondrial dynamics, and exopher production in neurons and provide insights for neurodegenerative diseases.

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“…Interestingly, a recent study introduced a potential neuroprotective role of EVs in assisting in the clearance of polyQ aggregates. Yang et al demonstrated that the inhibition of early-stage autophagy genes, excluding atg-16.2, triggers the secretion of exophers from neuronal cells of Caenorhabditis elegans to promote the excretion of polyQ aggregates, which consequently decreases the intracellular accumulation of polyQ aggregates [195].…”

Section: Role Of Evs In Pathophysiologymentioning

confidence: 99%

Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration

Shahi,

Kang,

Fonseka

2024

Cells

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Extracellular vesicles (EVs) are membrane-bound particles released by cells to perform multitudes of biological functions. Owing to their significant implications in diseases, the pathophysiological role of EVs continues to be extensively studied, leading research to neglect the need to explore their role in normal physiology. Despite this, many identified physiological functions of EVs, including, but not limited to, tissue repair, early development and aging, are attributed to their modulatory role in various signaling pathways via intercellular communication. EVs are widely perceived as a potential therapeutic strategy for better prognosis, primarily through utilization as a mode of delivery vehicle. Moreover, disease-associated EVs serve as candidates for the targeted inhibition by pharmacological or genetic means. However, these attempts are often accompanied by major challenges, such as off-target effects, which may result in adverse phenotypes. This renders the clinical efficacy of EVs elusive, indicating that further understanding of the specific role of EVs in physiology may enhance their utility. This review highlights the essential role of EVs in maintaining cellular homeostasis under different physiological settings, and also discusses the various aspects that may potentially hinder the robust utility of EV-based therapeutics.

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Autophagy protein ATG-16.2 and its WD40 domain mediate the beneficial effects of inhibiting early-acting autophagy genes in C. elegans neurons

Cited by 7 publications

References 70 publications

Distinct mechanisms of non-autonomous UPR^ERmediated by GABAergic, glutamatergic, and octopaminergic neurons

Distinct mechanisms of non-autonomous UPR^ERmediated by GABAergic, glutamatergic, and octopaminergic neurons

Non-apoptotic role of EGL-1 in exopher production and neuronal health inCaenorhabditis elegans

Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration

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Autophagy protein ATG-16.2 and its WD40 domain mediate the beneficial effects of inhibiting early-acting autophagy genes in C. elegans neurons

Cited by 7 publications

References 70 publications

Distinct mechanisms of non-autonomous UPRERmediated by GABAergic, glutamatergic, and octopaminergic neurons

Distinct mechanisms of non-autonomous UPRERmediated by GABAergic, glutamatergic, and octopaminergic neurons

Non-apoptotic role of EGL-1 in exopher production and neuronal health inCaenorhabditis elegans

Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration

Contact Info

Product

Resources

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Distinct mechanisms of non-autonomous UPR^ERmediated by GABAergic, glutamatergic, and octopaminergic neurons

Distinct mechanisms of non-autonomous UPR^ERmediated by GABAergic, glutamatergic, and octopaminergic neurons