Endocytic Adaptors in Cardiovascular Disease

Abstract

Endocytosis is the process of actively transporting materials into a cell by membrane engulfment. Traditionally, endocytosis was divided into three forms: phagocytosis (cell eating), pinocytosis (cell drinking), and the more selective receptor-mediated endocytosis (clathrin-mediated endocytosis); however, other important endocytic pathways (e.g., caveolin-dependent endocytosis) contribute to the uptake of extracellular substances. In each, the plasma membrane changes shape to allow the ingestion and internalization of materials, resulting in the formation of an intracellular vesicle. While receptor-mediated endocytosis remains the best understood pathway, mammalian cells utilize each form of endocytosis to respond to their environment. Receptor-mediated endocytosis permits the internalization of cell surface receptors and their ligands through a complex membrane invagination process that is facilitated by clathrin and adaptor proteins. Internalized vesicles containing these receptor-ligand cargoes fuse with early endosomes, which can then be recycled back to the plasma membrane, delivered to other cellular compartments, or destined for degradation by fusing with lysosomes. These intracellular fates are largely determined by the interaction of specific cargoes with adaptor proteins, such as the epsins, disabled-homolog 2 (Dab2), the stonin proteins, epidermal growth factor receptor substrate 15, and adaptor protein 2 (AP-2). In this review, we focus on the role of epsins and Dab2 in controlling these sorting processes in the context of cardiovascular disease. In particular, we will focus on the function of epsins and Dab2 in inflammation, cholesterol metabolism, and their fundamental contribution to atherogenicity.

Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein kinase C isozymes are involved in mGlu5a receptor internalization

“…Yet, how ubiquitination of mGlu5 facilitates receptor endocytosis is still unknown. Epsins, a family of clathrin adaptor proteins, mediate internalization via clathrincoated pits by binding ubiquitinated cargo through their ubiquitin-interacting motifs (51).…”

“…Yet, how ubiquitination of mGlu 5 facilitates receptor endocytosis is still unknown. Epsins, a family of clathrin adaptor proteins, mediate internalization via clathrin-coated pits by binding ubiquitinated cargo through their ubiquitin-interacting motifs ( 51 ). These adaptors might therefore support endocytosis of ubiquitinated mGlu 5 , like has been shown for proteinase-activated receptor 1 ( 52 ).…”

Targeting Epsins by nanotherapy regulates lipid metabolism and promotes ABCG1-mediated cholesterol efflux to fortify atheroma regression

“…The copyright holder for this preprint this version posted August 9, 2022. ; https://doi.org/10.1101/2022.08.09.503334 doi: bioRxiv preprint membrane PI (4,5) P2 (De Camilli et al, 2002;Itoh et al, 2001;Rosenthal et al, 1999), where it recognizes and recruits ubiquitinated cell surface receptors to clathrin-coated pits for internalization via its ubiquitin-interacting motif (UIM) and clathrin/AP-2 binding sites, respectively (Chen and De Camilli, 2005;Cui et al, 2020;Polo et al, 2002;Shih et al, 2002).…”

“…Epsins are a family of highly-conserved endocytic adaptor proteins that associate with the plasma membrane through interactions between their N-terminal homology (ENTH) domain and membrane PI (4,5) P2 (De Camilli et al, 2002; Itoh et al, 2001; Rosenthal et al, 1999), where it recognizes and recruits ubiquitinated cell surface receptors to clathrin-coated pits for internalization via its ubiquitin-interacting motif (UIM) and clathrin/AP-2 binding sites, respectively (Chen and De Camilli, 2005; Cui et al, 2020; Polo et al, 2002; Shih et al, 2002). Epsins 1 and 2 are ubiquitously expressed, redundant in function, and essential for embryonic survival (Chen et al, 2009).…”

Epsins Negatively Regulate Aortic Endothelial Cell Function by Augmenting Inflammatory Signaling

“…As receptor-mediated inflammatory signaling is central to the initiation and progression of atherosclerosis, and the uptake and sorting of EC surface receptors can fine-tune these signaling pathways [21][22][23][24][25][26][27], we focused our studies on the epsin family of clathrindependent endocytic adaptors [28][29][30]. In particular, epsins 1 and 2 modulate vascular endothelial growth factor receptor 2 (VEGFR2) signaling in ECs [21,23,24,26].…”