Although historically considered a receptor-induced process, it is now known that clathrin coats can spontaneously assemble at the PM and that cargo-to-clathrin interactions are important for the stabilization of the process. Clathrin-coated pits occupy 0.5–2% of the cell surface and provide the membrane-deforming scaffold, which is fundamental in shaping the coated pit at the plasma membrane [
13]. At the PM, clathrin assembles into a trimer of heterodimers, each unit consisting of one heavy and one light chain forming a triskelion [
14]. Triskelia assembly lead to the formation of a lattice-like structure around the vesicles and such assembly is coordinated by several cargo-binding adaptor complexes; the most known of these is represented by the adaptor protein complex 2 (AP2), which is part of a wider family of hetero-tetrameric adaptor complexes (AP1-5). AP2 binds both to clathrin and protein cargoes via a peptide motif in their cytoplasmic domains. Alternatively, clathrin adaptors can recruit client cargoes more selectively [
15]. These events are also strongly regulated by local actin and phosphoinositides on the plasma membrane. For instance, protein receptors clustering and phosphorylation recruits adaptin proteins at the plasma membrane, which initiates a cascade of low-affinity protein–protein and protein–lipid interactions (particularly with phosphatidylinositol 4,5-bisphosphate, PtdIns(4,5)P2), leading to the formation of a clathrin-coated pit (Smith et al., 2017). This is a highly dynamic and cooperative system in which a multitude of interactions form a pit within 30–120 s of ligand binding [
16]. Clathrin-coated pits at the cell surface are highly diverse and with respect to the usage of adaptor and associated proteins [
17]. This creates distinct microenvironments for the regulated entry of specific combinations of cargoes [
13,
18]. Moreover, ligand concentration also affects the mode of this endocytic route. For example, EGF is generally internalized by a clathrin-dependent endocytic route, but at higher concentrations, it enter cells through clathrin-independent routes [
18]. Once formed, the pit rapidly invaginates to form a clathrin-coated vesicle, which pinches off the plasma membrane through the activity of dynamin, a large mechanical GTPase. PtdIns(4,5)P2 phosphatases, notably synaptojanin, complete the vesicle cycle by uncoating the vesicles [
19]. Several viral pathogens such as the recent SARS-CoV-2 coronavirus and well-characterized families of virus (e.g., alpha-, rhabdo-, flavi-, picorna-, pox-, and adenoviruses, among others) enter cells by clathrin-mediated endocytosis, targeting receptors, or machineries internalized by the clathrin-dependent pathway [
20,
21]. For some pathogens, this route is obligatory, and for others, CME is one of the available escaping routes. Bacteria and large particles up to 1 μm in diameter have also been shown to co-opt clathrin and form actin-rich pedestals to facilitate their uptake [
21]. Although longer than the diameter of the typical clathrin-coated vesicle, these pathogens can be internalized by CME through the actin elongation of the clathrin-coated pit [
22]. The requirement for actin recruitment, although, can slow the endocytic process, leading to altered internalization kinetics, compared to conventional CME [
23].