An independent regulator of global release pathways in astrocytes generates a subtype of extracellular vesicles required for postsynaptic function

Abstract

Extracellular vesicles (EVs) are heterogeneous in size, composition, and function. We show that the six-transmembrane protein glycerophosphodiester phosphodiesterase 3 (GDE3) regulates actin remodeling, a global EV biogenic pathway, to release an EV subtype with distinct functions. GDE3 is necessary and sufficient for releasing EVs containing annexin A1 and GDE3 from the plasma membrane via Wiskott-Aldrich syndrome protein family member 3 (WAVE3), a major regulator of actin dynamics. GDE3 is expressed in astrocytes but not neurons, yet mice lacking GDE3 [ Gde3 knockout (KO)] have decreased miniature excitatory postsynaptic current (mEPSC) amplitudes in hippocampal CA1 neurons. EVs from cultured wild-type astrocytes restore mEPSC amplitudes in Gde3 KOs, while EVs from Gde3 KO astrocytes or astrocytes inhibited for WAVE3 actin branching activity do not. Thus, GDE3-WAVE3 is a nonredundant astrocytic pathway that remodels actin to release a functionally distinct EV subtype, supporting the concept that independent regulation of global EV release pathways differentially regulates EV signaling within the cellular EV landscape.

Annexin A1 may contribute to the morphological changes in podocytes by mediating endocytic vesicle fusion and transport via promotion of SNARE assembly in idiopathic membranous nephropathy

“…Third, we examined whether ANXA1 is present in vesicles in podocytes in IMN. Although ANXA1‐containing EVs have been reported to be involved in various pathological processes, 33,34 it is unknown whether ANXA1 is present in vesicles of podocytes in IMN. Fourth, the role of ANXA1 in SNARE assembly in podocytes of IMN is still unclear.…”

Rapid and in‐depth proteomic profiling of small extracellular vesicles for ultralow samples

“…Quantitative mass spectrometry (MS)‐based proteomics has contributed significantly to our understanding of the molecular composition and functionality of EVs. Proteomic studies have generated a wealth of knowledge in the EV field, providing unprecedented insights into cargo sorting mechanisms [9, 10], EV heterogeneity [8, 11–14], biogenesis [15], surfaceome [16, 17], interaction network [18], intracellular trafficking pathways [19], release (including organs [20, 21] / tissues [22]), targeting/localization [23], uptake, [24] and function [25, 26], to identifying specific marker proteins [27]. Their interrogation of EVs in biofluids has also highlighted their diagnostic potential [28–30] and therapeutic targets [31], establishing the role of EVs in health and disease.…”

Extracellular vesicles—An omics view

“…The form and function of EVs is marked by their proteome. Proteomic studies have generated new knowledge in the EV field, with exceptional insights into cargo sorting mechanisms [1, 2], EV heterogeneity and the subtypes and sub‐populations of EVs and particles [3–7], genesis [8], surfaceome [9, 10], interaction network [11], intracellular trafficking pathways [12], release (including organs [13, 14]/tissues [15]), targeting/localization [16], uptake [17] and function [18, 19], to identifying specific marker proteins [20]. Their interrogation of EVs in biofluids has also highlighted their diagnostic potential [21–23] and therapeutic targets [24], establishing the role of EVs in health and disease.…”