The Rubicon-WIPI axis regulates exosome biogenesis during aging
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ABSTRACT:
PROVIDER: PRJNA1093398 | ENA |
REPOSITORIES: ENA
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Project description:Cells release intraluminal vesicles (ILVs) in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNAi screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for ILV formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with aging and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for the age-dependent changes in exosome quantity and quality.
2024-06-25 | GSE262794 | GEO
Project description:Exosomes transport a variety of macromolecules and modulate intercellular communication in physiology and disease. However, the regulation mechanisms that determine exosome contents during exosome biogenesis remain poorly understood. Here, we identify GPR143, an atypical GPCR, as a regulator of the endosomal sorting complex required for transport (ESCRT)-dependent exosome biogenesis pathway. GPR143 interacts with HRS (an ESCRT-0 Subunit) and promotes its association to cargo proteins, such as EGFR, which subsequently enables selective protein sorting into intralumenal vesicles (ILVs) in multivesicular bodies (MVBs). GPR143 is elevated in multiple cancers and quantitative proteomic and RNA profiling of exosomes revealed the GPR143-ESCRT pathway promotes secretion of exosomes that carry unique cargo, including integrins signaling proteins. By gain- and loss-of-function studies, we reveal GPR143 promotes metastasis by secreting exosomes and increasing cell motility/invasion through the integrin/FAK/Src pathway. These finding uncover a mechanism that regulates the exosomal proteome and demonstrate its ability to promote cancer metastasis.
2022-12-20 | PXD031515 | Pride
Project description:The eukaryotic RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Autosomal recessive mutations in EXOSC3, EXOSC8, EXOSC9 and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. To understand the importance of the exosome in neurodegeneration, we investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are upregulated in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. In addition, exosome deficiency leads to increased levels of multiple non-coding RNAs (e.g. tRNAs, snoRNAs, scaRNAs). Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain and cerebellum caused by an increased number of apoptotic cells during development. Downregulation of EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. The work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis and p53-dependent signalling.
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Project description:The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer’s disease risk: the APOE4 allele increases risk while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in humans and mice. We hypothesized that the protective effects of APOE2 are mediated through the endosomal pathway during aging. In contrast to Alzheimer’s disease and APOE4 models, we detected normal morphology and abundance of early endosomes within cortical neurons of APOE2 targeted-replacement mice during aging despite decreased rab5b recruitment to early endosomes. Similarly, the morphology and abundance of retromer-associated vesicles was normal in APOE2 mice, despite reduced recruitment of vesicle-associated VPS35. Significantly, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, indicative of an enhanced endosomal cargo clearance to the extracellular space that contributes to a homeostatic balance of endosomal functions. Our findings thus demonstrate that APOE2 effectively offsets endosomal pathway changes during aging to preserve its integrity by enhancing exosome biogenesis, mitigating age-driven endosomal dysfunction that contributes to Alzheimer’s disease risk.
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Project description:NRDE2 negatively regulates nuclear exosome functions
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Project description:NRDE2 negatively regulates nuclear exosome functions IV
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Project description:NRDE2 negatively regulates nuclear exosome functions I
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Project description:In 12-month-old APOE targeted-replacement mice, we report that overall differences in gene expression were the most prominent when comparing the protective APOE2 to the other two alleles, with fewer differences found when comparing the risk-neutral APOE3 and disease-promoting APOE4 alleles. When compared with either APOE3 or APOE4, differential expression of genes within the endosomal pathways is a prominent feature of APOE2 expression in the brain. We hypothesized that the protective effects of APOE2 are mediated through the endosomal pathway during aging. In contrast to Alzheimer’s disease and APOE4 models, we detected normal morphology and abundance of early endosomes within cortical neurons of APOE2 targeted-replacement mice during aging despite decreased rab5b recruitment to early endosomes. Similarly, the morphology and abundance of retromer-associated vesicles was normal in APOE2 mice, despite reduced recruitment of vesicle-associated VPS35. Significantly, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, indicative of an enhanced endosomal cargo clearance to the extracellular space that contributes to a homeostatic balance of endosomal functions. Our findings thus demonstrate that APOE2 effectively offsets endosomal pathway changes during aging to preserve its integrity by enhancing exosome biogenesis, mitigating age-driven endosomal dysfunction that contributes to Alzheimer’s disease risk.
2023-07-31 | GSE188267 | GEO