Table 1 Follicular fluid exosome proteins involved in menopause-related cell signaling and inflammation
From: Menopause mysteries: the exosome-inflammation connection
Cellular function/pathway | Exosomal/Endosomal protein | Source | Mechanism of function | References |
|---|---|---|---|---|
TSAP6 (tumor suppressor associated pathway 6) | Endosome | Facilitates exosome secretion in response to DNA damage and oxidative stress. | ||
p53 pathway | Chmp4C (Charged multivesicular body protein 4C) | Endosome | Component of the ESCRT-3 complex. Aids MVB formation. | [124] |
Caveolin-1 | Mammalian cell | Caveolin-mediated endocytosis of cell-signaling mediators like TGF-β, Notch, IGF, EGFR proteins. | [124] | |
Wnt signaling | Membrane tetraspanins CD9 and CD82 | Exosome | Exosomal export of cellular β-catenin, downregulating Wntβ-catenin signaling | [56] |
TGF-β ligands | Exosome | Ferried by exosomes. Stimulate exosome secretion. | [139] | |
Clathrin, SNARE proteins | Mammalian cell | Clathrin-mediated endocytosis of TGF-β containing exosomes. | [76] | |
Caveolin | Mammalian cell | Caveolin mediated endocytosis of TGF-β exosomes. | [76] | |
TGF-β signaling | Heparan sulphate glycoproteins (membrane) | Exosome | Endosomal uptake of inactive TGF-β-LAP complex | [78] |
fibrinogens - fibronectins, fibrillins | Follicular fluid exosomes from PCOS affected females. | Cellular deposition of exosomal TGF-β-LAP complex. Promote fibrogenesis in the ovary. | [34] | |
thrombospondins kallikreins integrins | Follicular fluid exosomes from PCOS-afflicted females. | Activation of TGF-β, by cleaving LAP. Promote hyperfibrotic and pro-inflammatory conditions in the ovary. | [34] | |
connexin-43 (gap junction protein) | Granulosa cells | Form gap junctions between granulosa cells, and facilitate intercellular exosomal exchange. Upregulated by FSH and TGF-1. Downregulated by BMP-15 and GDF-9. | ||
Notch signaling | Notch ligands (Delta - DLLs, Serrate - Jagged 1 and 2, Lag) | Mammalian exosomes | Ferried by exosomes for sustained intercellular signaling. | |
Numb (Endosomal inhibitor of Notch) | Endosome | Promotes the trafficking of Notch ligands into late endosomes and lysosomes. Downregulated in ovarian cancers. | ||
PI3K/Akt signaling | COL6A1, HSP90AA1, HSP90AB1, HSP90B1, IGHM, ITGA2, ITGA6, ITGAV, ITGB1, ITGB3, RAC1, VTN, YWHAQ | Bovine follicular fluid exosomes | Proteins associated with exosome uptake. Upregulate PI3K/Akt signaling. | [37] |
Connexin-43 (gap junction protein) | Granulosa cells | Upregulated by Akt phosphorylation. | [96] | |
Insulin signaling | DENND1A.V2 | Porcine follicular fluid exosomes | Guanine nucleotide exchange factor for Rab35. Facilitates clathrin-mediated endocytosis. Elevated in PCOS. | [19] |
NLRP inflammasome cascade | NLRP protein complex or inflammasome | Ovary | Highly expressed in aged females. Stimulates the secretion of pro-inflammatory follicular fluid exosomes. | [142] |
Follicular fluid exosomes. | Carried and secreted by ovarian exosomes in response to decreased estrogen secretion. | [15] | ||
Oxidative stress | Sirtuins (1 and 2) | Ovary | Antioxidant. Downregulated with age. Negatively correlated with exosome biogenesis – in vitro knockdown of SIRT-1 and 2 promotes exosome secretion. | |
Inflammation | S100A9, S100A8 | Follicular fluid exosomes | Pro-inflammatory, anti-steroidogenic FF exosomal proteins. Upregulated with age. | |
peroredoxin (PRDX6, antioxidant enzyme) C reactive protein (CRP) d‐DOPA‐chrome decarboxylase (DDT) retinal dehydrogenase 1 (ALDH1A1) angiotensinogen TNF-α, kininogen‐1 (KNG1), S1009a | Follicular fluid exosomes | Pro-inflammatory exosomal proteins, activated in response to oxidative stress. Increased many-fold in FF exosomes of PCOS-affected individuals. | [32] | |
Heat shock response | HSP-70 | Exosomes | Activated against heat stress by nitric oxide (NO) signaling. Associated with vasomotor symptoms in menopause. Anti-inflammatory. Downregulated with age. | [130] |