Glycosylation and glycan interactions can serve as extracellular machinery facilitating clathrin-independent endocytosis.

In contrast to clathrin-mediated endocytosis (CME) which is well characterized and understood, little is known about the regulation and machinery underlying clathrin-independent endocytosis (CIE). There is also a wide variation in the requirements each individual CIE cargo has for its internalization. Recent studies have shown that CIE is affected by glycosylation and glycan interactions. We briefly review these studies and explore how these studies mesh with one another. We then discuss what this sensitivity to glycan interactions could indicate for the regulation of CIE. We address the spectrum of responses CIE has been shown to have with respect to changes in glycan interactions and attempt to reconcile disparate observations onto a shared conceptual landscape. We focus on the mechanisms by which cells can alter the glycan interactions at the plasma membrane and propose that glycosylation and glycan interactions could provide cells with a tool box with which cells can manipulate CIE. Altered glycosylation is often associated with a number of diseases and we discuss how under different disease settings, glycosylation-based modulation of CIE could play a role in disease progression. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.