Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier.

The blood-brain barrier (BBB) restricts clinically relevant accumulation of many therapeutics in the CNS. Low-dose methamphetamine (METH) induces fluid-phase transcytosis across BBB endothelial cells and could be used to enhance CNS drug delivery. Here, we show that low-dose METH induces significant BBB leakage in rodents and .

Listeria monocytogenes Exploits Host Caveolin for Cell-to-Cell Spreading.

moves from one cell to another using actin-rich membrane protrusions that propel the bacterium toward neighboring cells. Despite cholesterol being required for this transfer process, the precise host internalization mechanism remains elusive. Here, we show that caveolin endocytosis is key to this event as bacterial cell-to-cell transfer is severely impaired when cells are depleted of caveolin-1.

Vesicular trafficking plays a role in centriole disengagement and duplication.

Centrosomes are the major microtubule-nucleating and microtubule-organizing centers of cells and play crucial roles in microtubule anchoring, organelle positioning, and ciliogenesis. At the centrosome core lies a tightly associated or "engaged" mother-daughter centriole pair.  During mitotic exit, removal of centrosomal proteins pericentrin and Cep215 promotes "disengagement" by the dissolution of intercentriolar linkers, ensuring a single centriole duplication event per cell cycle.

Flotillin proteins recruit sphingosine to membranes and maintain cellular sphingosine-1-phosphate levels.

Sphingosine-1-phosphate (S1P) is an important lipid signalling molecule. S1P is produced via intracellular phosphorylation of sphingosine (Sph). As a lipid with a single fatty alkyl chain, Sph may diffuse rapidly between cellular membranes and through the aqueous phase.

EHD Proteins Cooperate to Generate Caveolar Clusters and to Maintain Caveolae during Repeated Mechanical Stress.

Caveolae introduce flask-shaped convolutions into the plasma membrane and help to protect the plasma membrane from damage under stretch forces. The protein components that form the bulb of caveolae are increasingly well characterized, but less is known about the contribution of proteins that localize to the constricted neck. Here we make extensive use of multiple CRISPR/Cas9-generated gene knockout and knockin cell lines to investigate the role of Eps15 Homology Domain (EHD) proteins at the neck of caveolae.

Architecture of the caveolar coat complex.

Caveolae are specialized membrane domains that are crucial for the correct function of endothelial cells, adipocytes and muscle cells. Caveolins and cavins are both required for caveolae formation, and assemble into a large (80S) caveolar coat complex (80S-CCC). The architecture of the 80S-CCC, however, has not been analyzed.

Caveolae: One Function or Many?

Caveolae are small, bulb-shaped plasma membrane invaginations. Mutations that ablate caveolae lead to diverse phenotypes in mice and humans, making it challenging to uncover their molecular mechanisms. Caveolae have been described to function in endocytosis and transcytosis (a specialized form of endocytosis) and in maintaining membrane lipid composition, as well as acting as signaling platforms.

Caveolae protect endothelial cells from membrane rupture during increased cardiac output.

Caveolae are strikingly abundant in endothelial cells, yet the physiological functions of caveolae in endothelium and other tissues remain incompletely understood. Previous studies suggest a mechanoprotective role, but whether this is relevant under the mechanical forces experienced by endothelial cells in vivo is unclear. In this study we have sought to determine whether endothelial caveolae disassemble under increased hemodynamic forces, and whether caveolae help prevent acute rupture of the plasma membrane under these conditions.

Dynamic caveolae exclude bulk membrane proteins and are required for sorting of excess glycosphingolipids.

Caveolae have long been implicated in endocytosis. Recent data question this link, and in the absence of specific cargoes the potential cellular function of caveolar endocytosis remains unclear. Here we develop new tools, including doubly genome-edited cell lines, to assay the subcellular dynamics of caveolae using tagged proteins expressed at endogenous levels.

Clathrin-independent pathways do not contribute significantly to endocytic flux.

Several different endocytic pathways have been proposed to function in mammalian cells. Clathrin-coated pits are well defined, but the identity, mechanism and function of alternative pathways have been controversial. Here we apply universal chemical labelling of plasma membrane proteins to define all primary endocytic vesicles, and labelling of specific proteins with a reducible SNAP-tag substrate.

Flotillin-1 facilitates toll-like receptor 3 signaling in human endothelial cells.

Endothelial cells are important elements in the vascular response to danger-associated molecules signaling through toll-like receptors (TLRs). Flotillin-1 and -2 are markers of membrane rafts but their true endothelial function is unknown. We hypothesized that flotillins are required for TLR signaling in human umbilical vein endothelial cells (HUVECs).

Cavin-3 knockout mice show that cavin-3 is not essential for caveolae formation, for maintenance of body composition, or for glucose tolerance.

The cavins are a family of proteins associated with caveolae, cavin-1, -2 and -3 being widely expressed while cavin-4 is restricted to striated muscle. Deletion of cavin-1 results in phenotypes including metabolic changes consistent with adipocyte dysfunction, and caveolae are completely absent. Deletion of cavin-2 causes tissue-specific loss of caveolae.

News from the caves: update on the structure and function of caveolae.

Recent data from the study of the cell biology of caveolae have provided insights both into how these flask-shaped invaginations of the plasma membrane are formed and how they may function in different contexts. This review discusses experiments that analyse the composition and ultrastructural distribution of protein complexes responsible for generating caveolae, that suggest functions for caveolae in response to mechanical stress or damage to the plasma membrane, that show that caveolae may have an important role during the signalling events for regulation of metabolism, and that imply that caveolae can act as endocytic vesicles at the plasma membrane. We also highlight unexpected roles for caveolar proteins in regulating circadian rhythms and new insights into the way in which caveolae may be involved in fatty acid uptake in the intestine.

The role of flotillins in regulating aβ production, investigated using flotillin 1-/-, flotillin 2-/- double knockout mice.

Flotillin 1 and flotillin 2 associate in the plasma membrane to form microdomains that have roles in cell signaling, regulation of cell-cell contacts, membrane-cytoskeletal interactions, and endocytosis. They are thought to be involved in the trafficking and hence processing of the Amyloid Precursor Protein, APP. In this study we set out to obtain in vivo confirmation of a link between flotillins and cleavage of APP to release amyloidogenic Aβ peptide, and to generate tools that would allow us to ask whether flotillins are functionally redundant.

Molecular composition and ultrastructure of the caveolar coat complex.

Caveolae are an abundant feature of the plasma membrane of many mammalian cell types, and have key roles in mechano-transduction, metabolic regulation, and vascular permeability. Caveolin and cavin proteins, as well as EHD2 and pacsin 2, are all present in caveolae. How these proteins assemble to form a protein interaction network for caveolar morphogenesis is not known.

Deletion of cavin genes reveals tissue-specific mechanisms for morphogenesis of endothelial caveolae.

Caveolae are abundant in endothelial cells and are thought to have important roles in endothelial cell biology. The cavin proteins are key components of caveolae, and are expressed at varied amounts in different tissues. Here we use knockout mice to determine the roles of cavins 2 and 3 in caveolar morphogenesis in vivo.

Cutaneous conditions leading to dermatology consultations in the emergency department.

Introduction: We established the most common cutaneous diseases that received dermatology consultation in the adult emergency department (ED) and identified differentiating clinical characteristics of dermatoses that required hospital admission.

Methods: A retrospective chart review of 204 patients presenting to the ED who received dermatology consultations at Los Angeles County/University of Southern California Medical Center, an urban tertiary care teaching hospital.

Results: Of all patients, 18% were admitted to an inpatient unit primarily for their cutaneous disease, whereas 82% were not.

The roles of flotillin microdomains--endocytosis and beyond.

Flotillins are membrane proteins that form microdomains in the plasma membrane of all mammalian cell types studied to date. They span the evolutionary spectrum, with proteins related to flotillins present in bacteria, fungi, plants and metazoans, which suggests that they perform important, and probably conserved, functions. Flotillins have been implicated in myriad processes that include endocytosis, signal transduction and regulation of the cortical cytoskeleton, yet the molecular mechanisms that underlie flotillin function in these different cases are still poorly understood.

Pacsin 2 is recruited to caveolae and functions in caveolar biogenesis.

The pacsin (also termed syndapin) protein family is well characterised structurally. They contain F-BAR domains associated with the generation or maintenance of membrane curvature. The cell biology of these proteins remains less understood.

SDPR induces membrane curvature and functions in the formation of caveolae.

Caveolae are plasma membrane invaginations with a characteristic flask-shaped morphology. They function in diverse cellular processes, including endocytosis. The mechanism by which caveolae are generated is not fully understood, but both caveolin proteins and PTRF (polymerase I and transcript release factor, also known as cavin) are important.

Molecular mechanisms of clathrin-independent endocytosis.

There is good evidence that, in addition to the canonical clathrin-associated endocytic machinery, mammalian cells possess multiple sets of proteins that are capable of mediating the formation of endocytic vesicles. The identity, mechanistic properties and function of these clathrin-independent endocytic pathways are currently under investigation. This Commentary briefly recounts how the field of clathrin-independent endocytosis has developed to date.