Insights of Endocytosis Signaling in Health and Disease

Abstract

Endocytosis in mammalian cells is a fundamental cellular machinery that regulates vital physiological processes, such as the absorption of metabolites, release of neurotransmitters, uptake of hormone cellular defense, and delivery of biomolecules across the plasma membrane. A remarkable characteristic of the endocytic machinery is the sequential assembly of the complex proteins at the plasma membrane, followed by internalization and fusion of various biomolecules to different cellular compartments. In all eukaryotic cells, functional characterization of endocytic pathways is based on dynamics of the protein complex and signal transduction modules. To coordinate the assembly and functions of the numerous parts of the endocytic machinery, the endocytic proteins interact significantly within and between the modules. Clathrin-dependent and -independent endocytosis, caveolar pathway, and receptor mediated endocytosis have been attributed to a greater variety of physiological and pathophysiological roles such as, autophagy, metabolism, cell division, apoptosis, cellular defense, and intestinal permeabilization. Notably, any defect or alteration in the endocytic machinery results in the development of pathological consequences associated with human diseases such as cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. In this review, an in-depth endeavor has been made to illustrate the process of endocytosis, and associated mechanisms describing pathological manifestation associated with dysregulated endocytosis machinery.

Keywords: chronic diseases; endocytosis; phagocytosis; pinocytosis; receptor endocytosis signaling.

Figure 1

Different pathways of endocytosis. Endocytosis can be broadly classified into pinocytosis and phagocytosis. Pinocytosis involves the internalization of small molecules, whereas phagocytosis involves the internalization of large particles like microbes. Receptor mediated endocytosis is a selective mechanism and the complex proteins recycled to cell membrane. Caveolin encapsulates transported molecules in the caveosomes and protects against lysosomal degradation. Clathrin-mediated endocytosis (CME) requires grafting of specific sorting sequences into membrane downturns and recruits clathrin moieties for cargo internalization.

Figure 2

Gene set enrichment analysis (GSEA) showing enriched gene sets of Rubcn KO and WT group comparison. Bars in red (positive NES) indicate significant enrichment in KO phenotype and bars in blue indicate WT phenotype (negative NES). Data source available fromGSE118019 [102].

Figure 3

Enrichment plot of top four GSEA hallmarks enriched in Rubcn knockout and wildtype. Rubcn KO group enriched with significant upregulation in apoptosis, glycolysis, hypoxia, and interferon gamma response gene sets (upper panel). Oxidative phosphorylation, p53, TGFβ signaling, and unfolded protein response enriched in WT group (lower panel).