Biology subjects

Verweij, F.

Publications and source records attributed to Verweij, F..

4 recordsLinked to original sources

bioRxiv2025

HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs

Amyloid precursor protein (APP) is a key player in various neuronal functions but also the source for toxic A{beta} that accumulates in the brain of Alzheimer patients. APP trafficking and processing depend on the endo-lysosomal system, but the molecular mechanisms that coordinate these processes remain unclear. Here, we studied the HOPS complex, a central regulator of endo-lysosomal maturation. We show that HOPS disruption impairs retromer-mediated recycling of APP to the TGN, resulting in the accumulation of APP in late endosomes. In neurons, this accumulation is spatially restricted to somatodendritic endosomes. These APP-containing endosomes are catalytically inactive and lack the {gamma}-secretase subunit PSEN2. However, they do contain BACE1, which leads to the build-up of toxic APP C-terminal fragments (APP-CTFs) upon HOPS disruption. Notably, loss of HOPS enhances secretion of APP-CTFs by exosomes, suggesting a potential mechanism for disease propagation. Together, our findings establish a mechanistic link between HOPS dysfunction and aberrant APP processing, with implications for neurodegeneration. HighlightsO_LIHOPS KO impairs retromer-mediated APP recycling to the TGN C_LIO_LIHOPS disruption redistributes APP to somatodendritic stationary late endosomes C_LIO_LIHOPS depletion increases APP and BACE1 convergence, causing APP-CTF accumulation C_LIO_LIThese APP-CTFs accumulate in catalytically inactive endosomes that lack PSEN2 C_LIO_LIAPP-CTFs are secreted via exosomes, potentially promoting disease propagation C_LI

cell biology↗

bioRxiv2024

Caveolin-1 and mechanical stress control the release of a pro-metastatic subpopulation of small extracellular vesicles

Mechanical forces within the tumor microenvironment critically influence cancer progression, in part by modulating extracellular vesicle (EV) dynamics. However, the molecular mechanisms by which EVs respond to mechanical cues remain poorly understood. Here, we identify caveolin-1 (Cav1), a core structural component of caveolae, specialized membrane invaginations that act as mechanosensors, as a key regulator of EV release and composition under mechanical stress. We demonstrate that both 2D osmotic shock and 3D mechanical compression significantly enhance EV secretion from cancer cells in a Cav1-dependent manner. These EVs exhibit a distinct lipid profile and are selectively enriched in proteins involved in cell adhesion, motility, wound healing and extracellular matrix remodeling, cargo that is lost upon Cav1 deletion. Functionally, EVs secreted from mechanically stressed cells preferentially accumulate in the liver in vivo and promote breast cancer cell migration and invasion in vitro, effects abolished in the absence of Cav1. Together, these findings reveal a previously unrecognized role for Cav1 in coupling mechanical stress to EV biogenesis and cargo loading, thereby promoting metastatic traits. This study underscores a novel mechanism by which mechanical cues within tumor environment regulate EV-mediated communication and suggests that Cav1-enriched EVs may contribute to pre-metastatic niche formation.

cancer biology↗

bioRxiv2020

Specificities of exosome versus small ectosome secretion revealed by live intracellulartracking and synchronized extracellular vesicle release of CD9 and CD63

Despite their important and multiple roles in intercellular communications, the different populations of extracellular vesicles (EVs) and their secretion mechanisms are not fully characterized yet. In particular, how and to what extent EVs form either as intraluminal vesicles of endocytic compartments (exosomes), or at the plasma membrane (ectosomes) remains unclear. We followed in HeLa cells the intracellular trafficking of the EV markers CD9 and CD63 from the endoplasmic reticulum to their residency compartment and identified transient co-localization both at the plasma membrane (PM) and in endosomes, before they finally segregate. CD9 was more abundantly released in EVs than CD63. However, when forcing expression of CD63 at the PM, by mutating its lysosome-addressing motive, its secretion in EVs was increased. Thus, in HeLa cells, small ectosomes are more prominently released than exosomes. By comparative proteomic analysis, we identified a few surface proteins likely specific of either exosomes (e.g. LAMP1) or ectosomes (e.g. BSG, SLC3A2), based on their known intracellular location in lysosomes or the PM, and on the different effects on their release of Bafilomycin A1, a drug that neutralizes endosomal pH. Our work sets the path for molecular and functional discrimination of exosomes and small ectosomes in any cell type.

cell biology↗

bioRxiv2019

Origin of bidirectionality of cerebrospinal fluid flow and impact on long-range transport between brain and spinal cord

The circulation of cerebrospinal fluid (CSF) plays pivotal roles for body axis formation and brain development. During embryogenesis, CSF is rich in particles and proteins and flows bidirectionally in the central canal. The origins of bidirectional flow and its impact on development are unknown. Experiments combined with modeling and simulations demonstrate that the bidirectionality of CSF flow is generated locally by caudally-polarized motile cilia confined to the ventral wall of the central canal. Such active bidirectional flow of the CSF accelerates the long-range transport of particles propagating rostrally and caudally. In addition, spontaneous muscle contractions increase local CSF flow and consequently enhance long-range transport of extracellular lipidic particles. Focal ablation of the channel connecting brain ventricles to the central canal reduces embryo length, indicating that long-range transport contributes to embryonic growth. Our study also demonstrates that at this early stage, motile cilia ensure the proper formation of the central canal.

biophysics↗