Comparative analysis of PTMs in EV cargo selection.
| PTM type | Key regulatory proteins | Molecular mechanism | Cargo selection specificity | Impact on EV content | Neurological relevance | Key references |
|---|---|---|---|---|---|---|
| UBL3 modification | UBL3 (membrane-anchored ubiquitin-fold protein) | Geranylgeranylation-dependent membrane anchoring promotes protein-membrane association via the C-terminal CAAX motif | Broad spectrum: > 1,200 interactors; ~30% are EV cargo proteins, including Ras, α-synuclein, mHTT | ~60% reduction in sEV protein content upon knockout | α-synuclein (PD), mHTT (HD); interaction upregulated under oxidative stress | [18, 20] |
| Ubiquitination | ESCRT-0, ALIX, TSG101, MARCH E3 ligases | Recognition of ubiquitinated membrane proteins; ESCRT complex recruitment for MVB sorting | Selective for ubiquitin-tagged transmembrane proteins; MHC-II molecules | Essential for ESCRT-dependent exosome formation | Immune molecule sorting; potential role in neuroinflammation | [53, 54] |
| SUMOylation | SUMO-2, SUMO-conjugating enzymes | Covalent attachment of SUMO moieties facilitates ESCRT interactions | hnRNPA2B1-mediated miRNA sorting via specific motifs; α-synuclein, APP sorting | Controls specific miRNA profiles (e.g., miR-146a) and protein aggregates | miRNA-mediated neuroinflammation; α-synuclein propagation (PD); APP processing (AD) | [58, 65] |
| Palmitoylation | Palmitoyl acyltransferases (PATs) | S-acylation with palmitate enhances hydrophobic membrane interactions | Membrane-associated proteins; tetraspanins (CD9, CD63, CD81) | Governs protein-membrane dynamics and clustering in lipid rafts | Tetraspanin-mediated EV formation; potential role in synaptic vesicle release | [57, 58] |
| Glycosylation | Glycosyltransferases | N- or O-linked glycan addition to transmembrane proteins | Surface glycoproteins: EWI-2 and other tetraspanin partners | Determines EV targeting, uptake specificity, and immunological recognition | BBB targeting, microglial uptake specificity, neuroimmune interactions | [66] |
AD: Alzheimer’s disease; APP: amyloid precursor protein; BBB: blood-brain barrier; ESCRT: endosomal sorting complex required for transport; EV: extracellular vesicle; HD: Huntington’s disease; hnRNPA2B1: heterogeneous nuclear ribonucleoprotein A2/B1; MARCH: membrane-associated RING-CH; MHC: major histocompatibility complex; miRNA: microRNA; mHTT: mutant huntingtin; MVB: multivesicular body; PD: Parkinson’s disease; PTMs: post-translational modifications; sEV: small EV; UBL3: ubiquitin-like protein 3.
MAM: Writing—original draft, Writing—review & editing, Visualization. MMH: Conceptualization, Writing—original draft, Writing—review & editing, Visualization. Both authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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