Unconventional Functions for Clathrin, ESCRTs, and Other Endocytic Regulators in the Cytoskeleton, Cell Cycle, Nucleus, and Beyond: Links to Human Disease

Abstract

The roles of clathrin, its regulators, and the ESCRT (endosomal sorting complex required for transport) proteins are well defined in endocytosis. These proteins can also participate in intracellular pathways that are independent of endocytosis and even independent of the membrane trafficking function of these proteins. These nonendocytic functions involve unconventional biochemical interactions for some endocytic regulators, but can also exploit known interactions for nonendocytic functions. The molecular basis for the involvement of endocytic regulators in unconventional functions that influence the cytoskeleton, cell cycle, signaling, and gene regulation are described here. Through these additional functions, endocytic regulators participate in pathways that affect infection, glucose metabolism, development, and cellular transformation, expanding their significance in human health and disease.

Forty Years of Clathrin‐coated Vesicles

“…For instance, intracellular CCVs contain a lot of SNAREs that don't seem to be able to bind to epsinR or CALM , so are there other SNARE‐adaptor interactions we don't know about? And how many of the pieces of the core machinery have additional functions ? Clathrin heavy chain can ‘moonlight’ as a component of the mitotic spindle , while some of the other coat components, like epsin and CALM, can get inside the nucleus .…”

A unique role for clathrin light chain A in cell spreading and migration

“…These include mediating endocytosis of diverse cargoes from coated pits in the plasma membrane, sorting of biosynthetic cargoes from coated buds in the trans-Golgi network (TGN), and roles in intracellular trafficking pathways from coated tubular and vacuolar domains on sorting endosomes to other compartments in the endolysosomal network (Klumperman and Raposo, 2014;Schreij et al, 2016). In addition, non-canonical roles for clathrin that have been more recently recognized include stabilization of the mitotic spindle in dividing cells (Royle, 2012;Royle et al, 2005), WAVE complex-mediated lamellipodium formation and migration in lymphocytes (Gautier et al, 2011;Ramirez-Santiago et al, 2016), anchorage to collagen fibers in cells migrating in 3D environments (Elkhatib et al, 2017) and others (Brodsky et al, 2014). Given this diversity, understanding the determinants for clathrin action in these and potentially other novel clathrin functions are important goals.…”

Endocytosis: Past, Present, and Future

“…Not surprisingly, given its evolutionary importance, as suggested by de Duve, many of the proteins that drive endocytosis are highly conserved and can be traced to the earliest eukaryotic ancestors; more recent additions to the endocytic machinery are likely indicative of specialization and increased regulation of the endocytic pathways during evolution (as discussed in the article by Wideman et al 2014). Some components of the endocytic machinery play "moonlighting" functions in divergent cellular processes (see Brodsky et al 2014). Whether these components reflect their ancestral functions and the origins of the endocytic machinery, or new vocations, remains to be determined.…”