Biology subjects

Viaris de Lesegno, C.

Publications and source records attributed to Viaris de Lesegno, C..

5 recordsLinked to original sources

bioRxiv2025

Palmitoylated caveolin-1 enables endosome sorting of complex sphingolipids

Complex sphingolipids form in the Golgi apparatus and require transport by vesicular carriers to reach the plasma membrane (PM) where they assemble with cholesterol to affect membrane function. The caveolin proteins have been implicated in sphingolipid trafficking but by mechanisms unknown. Here, we found that cells lacking caveolin-1 (Cav1) distributed the complex sphingolipids to the lysosome rather than to the PM. This was not seen in Cavin-1 KO cells, implicating a function for Cav1 independent of caveolae. The defect in trafficking localized to the sorting endosome where the complex sphingolipids failed to enter recycling tubules serving the PM. Sphingolipid trafficking was rescued by over-expression of Cav1, but not by a Cav1 mutant that lacked the S-palmitoylation sites. Thus, noncaveolar and palmitoylated Cav1 appears to act as a chaperone, or selectivity filter, enabling entry of the complex sphingolipids into endocytic recycling tubules to shape the composition of the PM.

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↗

bioRxiv2019

Caveolae coupling of melanocytes signaling and mechanics is required for human skin pigmentation

Tissue homeostasis requires regulation of cell-cell communication, which relies on signaling molecules and cell contacts. In skin epidermis, keratinocytes secrete specific factors transduced by melanocytes into signaling cues to promote their pigmentation and dendrite outgrowth, while melanocytes transfer melanin pigments to keratinocytes to convey skin photoprotection. How epidermal cells integrate these functions remains poorly characterized. Here, we found that caveolae polarize in melanocytes and are particularly abundant at melanocyte-keratinocyte interface. Caveolae in melanocytes are sensitive to ultra-violet radiations and miRNAs released by keratinocytes. Preventing caveolae formation in melanocytes results in increased production of intracellular cAMP and melanin pigments, but decreases cell protrusions, cell-cell contacts, pigment transfer and epidermis pigmentation. Altogether, our data establish that, in melanocytes, caveolae serve as key molecular hubs that couple signaling outputs from keratinocytes to mechanical plasticity. This process is crucial to maintain cell-cell contacts and intercellular communication, skin pigmentation and tissue homeostasis.

cell biology↗

bioRxiv2019

STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by type I interferons (IFN) requires clathrin-dependent endocytosis of the IFN-/{beta} receptor (IFNAR). The molecular machinery that brings about the selective activation of IFN-/{beta}-induced JAK/STAT signaling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and the TYK2 Janus kinase at the plasma membrane prevents the activation of TYK2 by type I IFNs. IFN- stimulated endocytosis leads to the interaction of IFNAR1 with Hrs on early endosomes, which then relieves TYK2 inhibition by STAM and thereby allows for TYK2 and IFNAR signaling. In contrast, IFN-{beta} stimulation results in sorting of IFNAR to a distinct endosomal subdomain where the receptor is activated independently from Hrs. Our results identify the molecular machinery that controls the spatiotemporal activation of TYK2 and establish the central role of endosomal sorting in the differential regulation of JAK/STAT signaling by IFN- and IFN-{beta}.\n\nSummaryThe spatiotemporal activation of JAK/STAT signaling by IFN- is controlled by STAM association with Hrs at the early endosome.

cell biology↗

bioRxiv2018

Lack of functional caveolae in Cav3 mutated human dystrophic myotubes results in deficient mechanoprotection and IL6/STAT3 mechanosignaling.

Caveolin-3 is the major structural protein of caveolae in muscle cells. Mutations in the CAV3 gene cause different type of muscle disorders mostly characterized by defects in membrane integrity and repair, deregulation in the expression of various muscle proteins and deregulation of several muscle associated signaling pathways. We show here that myotubes derived from patients bearing the CAV3 P28L and R26Q mutations present a lack of functional caveolae at the plasma membrane which results in an abnormal mechanoresponse. Mutant myotubes can no longer buffer the increase of membrane tension induced by mechanical stress and present an hyperactivation of the IL6/STAT3 signaling pathway at rest and under mechanical stress. The impaired mechanical regulation of the IL6/STAT3 signaling pathway by caveolae leads to chronic activation and a higher expression of muscle specific genes. These defects could be reversed by reassembling a pool of functional caveolae through expression of wild type Cav3. Our findings bring more mechanistic insight into human Cav3 associated muscle disorders and show a general defect in the mechanoresponse of CAV3 P28L and R26Q myotubes.

cell biology↗