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PreprintCited by 6Cellular transport and secretionExtracellular vesicles in diseaseUbiquitin and proteasome pathways

Accessory ESCRT-III proteins selectively regulate Rab11-exosome biogenesis in Drosophila secondary cells

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Marie, Pauline P., Fan, Shih-Jung, Mendes, Claudia C., Wainwright, S. Mark, Harris, Adrian L., Goberdhan, Deborah C. I., Wilson, Clive·2020·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2020.06.18.158725
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Abstract

Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in multivesicular endosomes, which subsequently fuse with the plasma membrane. These ILVs are made in both late endosomes and recycling endosomes, the latter marked by the small GTPase Rab11 and generating exosomes with different cargos and functions. Core proteins within four Endosomal Sorting Complex Required for Transport (ESCRT) assemblies (0-III) play key sequential roles in late endosomal exosome biogenesis and ILV-mediated destruction of ubiquitinylated cargos through the endolysosomal system. They also control additional cellular processes, such as cytokinesis and other vesicle budding. By contrast, the functions of several accessory ESCRTs are not well defined. Here we assess the ESCRT-dependency of Rab11-exosomes, using RNA knockdown in Drosophila secondary cells (SCs) of the male accessory gland, which have unusually enlarged Rab11-positive compartments. Unexpectedly, not only are core proteins in all four ESCRT complexes required for Rab11-exosome formation, but also accessory ESCRT-III proteins, CHMP1, CHMP5 and IST1. Suppressing expression of these accessory proteins does not affect other aspects of cell morphology, unlike most core ESCRT knockdowns, and does not lead to accumulation of ubiquitinylated cargos. We conclude that accessory ESCRT-III components have a specific and potentially ubiquitin-independent role in Rab11-exosome generation, which might provide a target for blocking the pro-tumorigenic activities of these vesicles in cancer.

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  • Exosome and DCG biogenesis are inter-dependent.

    “consistent with recent ESCRT knockdown experiments in SCs47, which suggest that exosome and DCG biogenesis are inter-dependent.”

    From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [47]

    In 'Core ESCRTs control Rab11- and late endosomal exosome biogenesis' (page unavailable), the paper says dense-core granule formation and Rab11-exosome biogenesis appear functionally associated, and several ESCRT knockdowns affect both. It also says the link is not understood and that some knockdowns strongly suppress intraluminal vesicle formation without changing DCG number. The experiments therefore suggest an association, but do not establish that the two processes are inter-dependent. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Formation and clustering of ILVs and DCG biogenesis in Rab11 compartments of secondary cells are regulated by GAPDH2 and appear functionally linked.

    “Overall, our data indicate that the formation and clustering of ILVs and DCG biogenesis in Rab11 compartments of SCs are regulated by GAPDH2 and appear to be functionally linked processes, a result supported by a recent analysis of ESCRT function in SCs47.”

    From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [47]

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  71. Yuan, J., Ma, J., Zheng, H., Shi, T., Sun, W., Zhang, Q., Lin, D., Zhang, K., He, J., Mao, Y., Gao, X., Gao, P., Han, N., Fu, G., Xiao, T., Gao, Y., Ma, D., Cheng, S., 2008. Overexpression of OLC1, Cigarette Smoke, and Human Lung Tumorigenesis. JNCI J. Natl. Cancer Inst. 100, 1592-1605. https://doi.org/10.1093/jnci/djn379 Panels A-I show basal wide-field fluorescence views of living SCs expressing YFP- Rab11 from its endogenous genomic location (yellow). SC outline approximated by dashed white circles. Acidic compartments are marked by LysoTracker® Red (magenta, Merge). Boxed non-acidic compartments are magnified in A'-H'. (A) Control SC expressing rosy-RNAi. YFP-Rab11-positive ILV puncta are observed inside nearly 50% of Rab11-compartments (arrowheads; A'). (B) SC expressing Stam-RNAi. YFP- Rab11-positive ILVs are reduced. (C) SC expressing TSG101-RNAi. YFP-positive ILVs are reduced. (D) SC expressing Vps36-RNAi. YFP-Rab11-positive ILVs are reduced. (E) SC expressing Usp8-RNAi. YFP-Rab11-positive ILVs are reduced. (F) SC expressing Chmp2-RNAi. YFP-Rab11-positive ILVs are reduced. (G) SC expressing Vps20-RNAi. YFP-Rab11-positive ILVs are reduced. (H) SC expressing Vps24-RNAi. YFP-Rab11-positive ILVs are reduced. (I) SC expressing Ist1-RNAi. YFP-Rab11-positive ILVs are reduced. All data are from 6-day-old males shifted to 29°C at eclosion to induce transgene expression. Genotypes are: w; P[w + , tub- GAL80ts]/+; dsx-GAL4/TI{Tl}Rab11EYFP with RNAi #1 lines for each gene. Scale bars in A-I, 10 µm and in A'-I', 1 µm. RNAi strongly accumulates ubiquitin in cytosol and some Btl-GFP-positive compartments. (E) SC expressing Vps20-RNAi accumulates ubiquitin in cytoplasm. (F) SC expressing Ist1-RNAi does not accumulate ubiquitin in the cytoplasm. All data are from 6-day-old male flies shifted to 29°C at eclosion to induce transgene expression. Genotypes are: w; P[w + , tub-GAL80ts]/+; dsx-GAL4/P[w + , UAS-btl-GFP] with rosy-or RNAi #1 lines. Scale bars in A-F, 10 µm. · DOI

Cited by

Sorted by citations

Authors
Marie, P. P., Fan, S.-J., Mendes, C. C., Wainwright, S. M., Harris, A. L., Goberdhan, D. C. I., & Wilson, C.
Affiliations
University of Oxford (GB)
Corresponding author
Wilson, Clive
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2020-06-18
DOI
10.1101/2020.06.18.158725
OpenAlex
W3036691395
Cited by
6
References
5
Citations by year
2026: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 1
Type
posted content
Language
en
Open access
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders
  • Wellcome Trust (107457, 091911)
  • Cancer Research UK (BB/K017462/1, C19591/A19076, C602/A18974, A18974, A19076)
  • Biotechnology and Biological Sciences Research Council (BB/N016300/1, BB/R004862/1, BB/K017462/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
exosome biogenesis, Rab11, CHMP5, IST1, multivesicular endosomes, recycling endosomes, intraluminal vesicles, male accessory glands, carcinogenesis

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