Vesicle Makeover!

In the brain, cells communicate by sending out packages called small extracellular vesicles (sEVs). They carry vital protein signals that dictate how neurons grow and repair themselves. These messengers are often remodelled by molecular scissors called proteases. The Optobiology Group (Marina Mikhaylova) investigated how the enzyme A Disintegrin And Metalloprotease 10 (ADAM10) acts as a master sculptor, trimming surface proteins to change how these vesicles deliver their messages. This process is key to understanding both healthy brain function and neurodegenerative disease. They showed that ADAM10 actively reshapes the protein landscape of brain-derived vesicles. Using advanced proteomics, the researchers discovered that ADAM10 cleaves a wide variety of adhesion and signaling molecules directly on the vesicles after they are released. This allows the brain to dynamically alter cell-to-cell communication, suggesting that ADAM10 is a critical regulator of how messages are received and processed in the neural network. Read more about ADAM10 in the Journal of Extracellular Biology.

Abstract

Proteases are common components of extracellular vesicles (EVs), yet the extent and functional relevance of ongoing proteolytic activity on EV surfaces remain largely unexplored. Such activity could significantly influence EV function and identity, with likely implications for EV-mediated signalling, recipient cell targeting, cargo delivery, and even translational applications ranging from biomarker discovery to therapeutic approaches. Here, we investigated the impact of sustained proteolysis on the composition of brain cell-derived EVs, focusing on A Disintegrin And Metalloprotease 10 (ADAM10), a key sheddase for signalling and adhesion proteins involved in neuronal and synaptic processes. Using primary rat cortical cultures, we found that numerous known ADAM10 substrates are part of small EVs (sEVs), and that their associated functions overlap with major sEV-mediated roles such as nervous system development, cell adhesion, and neurite outgrowth. Applying N-terminal proteomics to monitor sEV-derived cleavage fragments over time, we identified novel substrate candidates and demonstrated that sEV-associated ADAM10 activity remodels surface proteins involved in EV-cell interactions while generating soluble factors implicated in neuronal development. These findings suggest a previously unrecognised role for ADAM10 as a modulator of sEV composition and potentially cell-targeting specificity in the brain and position EVs as dynamic platforms for proteolytic processing ‘on the move’.