Muscle‐derived exophers promote reproductive fitness

Turek, Michał; Banasiak, Katarzyna; Piechota, Małgorzata; Shanmugam, Nilesh; Macias, Matylda; Śliwińska, Małgorzata Alicja; Niklewicz, Marta; Kowalski, Konrad; Nowak, Natalia; Chacińska, Agnieszka; Pokrzywa, Wojciech

doi:10.15252/embr.202052071

Cited by 25 publications

(36 citation statements)

References 41 publications

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“…These structures suggested that while the exophers still are connected to the parent cell, small "packages" of cellular material may be added to the main exophers, similar to a phenomenon described recently in c. elegans muscle-cell exophers 8 .…”

Section: Introductionsupporting

confidence: 68%

“…Our findings suggest that in addition to their roles in removal of unwanted cellular components 1,9 or supporting nematode embryos 8 , a basal, innate level of exopher formation exists in young, wild-type mouse neurons (Fig. 3d) and human neuroblastoma cells (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 83%

“…Follow-up studies in c. elegans showed that neuronal exopherogenesis also can be induced by nutrient deprivation and may be controlled by specific, non-cell autonomous signaling pathways related to lipid synthesis and/or the fibroblast growth factor/RAS/MAPK pathway 7 . Body-wall muscle cell exophers were observed in c. elegans to support embryo development 8 , and exophers of mouse and human cardiomyocytes also were reported to expel damaged mitochondria and other cargo to be taken up by macrophages 9 . However, it has been unknown if exophers exist in the mammalian brain, if they indeed assist in removal of cell debris under proteostatic stress as observed in c. elegans , and whether they also have a role in normal physiology, other than the recently reported nematode embryo support.…”

Section: Introductionmentioning

confidence: 99%

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Exophers are components of mammalian cell neurobiology in health and disease

Siddique¹,

Di²,

Williams³

et al. 2021

Preprint

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Maintenance of cellular homeostasis is critically important for the survival of cells and organisms. Degradation and recycling of biomolecules and whole organelles is an essential mechanism for maintaining cellular homeostasis. The main systems responsible for these processes are the ubiquitin-proteasome system and autophagy-lysosome pathway. Another mechanism was reported in c. elegans--formation of large, membrane-enclosed projections called exophers, into which cells direct debris and toxic protein aggregates. Exophers were shown to act as large, temporary disposal compartments that disconnected from the cells within several hours. Here, we report the discovery of exophers in the mammalian brain, including the brains of humans and mice. Similar to those described in nematodes, the mammalian exophers appear to emanate from the cell body, initially connected by a nanotube, and eventually disconnect. Rare, innate exophers were found in healthy human brain and primary neurons from wild-type mice, presumably mediating transfer of large cargo between cells. The number of exophers increased as an adaptive response under proteostatic stress, e.g., in Alzheimer's disease brain or in primary neurons from two tauopathy mouse models, where the exophers likely facilitated expulsion of proteotoxic material. Our findings suggest that exopherogenesis is a rare, innate house-keeping process that is elevated adaptively in response to proteostatic pressure and is a conserved mechanism from nematodes to humans.

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Section: Introductionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exophers are components of mammalian cell neurobiology in health and disease

Siddique¹,

Di²,

Williams³

et al. 2021

Preprint

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“…A recent report implicates reproduction in muscle exopher production ( 75 ) consistent with a role for germline in nonautonomous regulation of exopher-inducing signals.…”

Section: Data Availabilitymentioning

confidence: 70%

Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling

Cooper

Guasp

Arnold

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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In human neurodegenerative diseases, neurons can transfer toxic protein aggregates to surrounding cells, promoting pathology via poorly understood mechanisms. In Caenorhabditis elegans, proteostressed neurons can expel neurotoxic proteins in large, membrane-bound vesicles called exophers. We investigated how specific stresses impact neuronal trash expulsion to show that neuronal exopher production can be markedly elevated by oxidative and osmotic stress. Unexpectedly, we also found that fasting dramatically increases exophergenesis. Mechanistic dissection focused on identifying nonautonomous factors that sense and activate the fasting-induced exopher response revealed that DAF16/FOXO-dependent and -independent processes are engaged. Fasting-induced exopher elevation requires the intestinal peptide transporter PEPT-1, lipid synthesis transcription factors Mediator complex MDT-15 and SBP-1/SREPB1, and fatty acid synthase FASN-1, implicating remotely initiated lipid signaling in neuronal trash elimination. A conserved fibroblast growth factor (FGF)/RAS/MAPK signaling pathway that acts downstream of, or in parallel to, lipid signaling also promotes fasting-induced neuronal exopher elevation. A germline-based epidermal growth factor (EGF) signal that acts through neurons is also required for exopher production. Our data define a nonautonomous network that links food availability changes to remote, and extreme, neuronal homeostasis responses relevant to aggregate transfer biology.

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“…A recent study reported that body wall muscles (BWM) of young adult worms can synthesize VIT-2, and transport it to oocytes via VIT-2-containing exophers, to promote the development of offspring (Turek et al, 2021). However, our anti-VIT-1/2 immuno-EM analysis did not find evidence for this claim.…”

Section: Discussionmentioning

confidence: 99%

Immuno-electron microscopy localizes Caenorhabditis elegans vitellogenins along the classic exocytosis route

Zhai

Zhang

et al. 2022

Preprint

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Vitellogenins (VITs) are the most abundant proteins in adult hermaphrodite C. elegans. VITs are synthesized in the intestine, secreted to the pseudocoelom, matured into yolk proteins (YPs), and finally deposited in oocytes to support embryonic and larval development. How VITs are secreted out of the intestine remains unclear. In this study, we use immuno-electron microscopy (immuno-EM) to characterize the wild-type subcellular structures containing VITs or YPs. In the intestinal cells of young adult worms, we identify VITs along an exocytic pathway consisting of the rough ER, the Golgi, and the lipid bilayer bounded vesicles, which we call intestinal vitellogenin vesicles (VVs). This suggests that the classic exocytotic pathway mediates secretion of VITs from the intestine to the pseudocoelom. We also show that pseudocoelomic yolk patches (PYPs) are membrane-less and amorphous. The different VITs/YPs are packed as a mixture into the above structures. The size of VVs can vary with the VIT levels and the age of the worm. On adult day 2 (AD 2), intestinal VVs (∼200 nm in diameter) are smaller than gonadal yolk organelles (YOs, ∼500 nm in diameter). VVs, PYPs, and YOs share a uniform, medium electron density by conventional EM. The morphological profiles documented in this study can serve as a reference for future studies of VITs/YPs. Surveying the findings from this study and elsewhere, we review in the discussion the post-translational modifications and protein-protein interactions of C. elegans VITs/YPs.

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Muscle‐derived exophers promote reproductive fitness

Cited by 25 publications

References 41 publications

Exophers are components of mammalian cell neurobiology in health and disease

Exophers are components of mammalian cell neurobiology in health and disease

Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling

Immuno-electron microscopy localizes Caenorhabditis elegans vitellogenins along the classic exocytosis route

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