Fig. 5

Internalization of the virus using Clathrin-dependent endocytosis (A). Virus attachment to a wide variety of cell receptors can induce activation and autophosphorylation of Src. Interaction of Src with cell surface receptors drives phosphorylation of receptors and activation of the PI3K/Akt/mTOR signaling pathway. PI3-K via activation of cCbl (E3ubiquitin ligase) multi-ubiquitylates EGFR, which drives phosphorylation and ubiquitination of receptor, then translocates virus bonded receptors into lipid raft. Ubiquitinated receptor drives phosphorylation and monoubiquitylation of EPS15 and monoubiquitylation of epsin. Epsin is a scaffold protein and binds to PI(4,5)₂P in lipid rafts, cargo receptors, Esp15, AP2 protein, and clathrin molecules. Furthermore, the interaction of ESP15 with FCHO and intersectin proteins forms a trimeric FCHo/Eps15/ intersectin complex that can interact with AP2. Thus, AP2 is recruited for attachment to the membrane receptors and Clathrin molecules via interaction with FCHo/Eps15/ intersectin complex and Epsin proteins. Nucleation of AP2 can increase the local concentration of PIP2 by incrementing the activity of PIP kinase. Membrane fission of clathrin-coated vesicles is followed by the formation of dynamin helical oligomers at the neck of vesicles. After scission, vesicles are uncoated by the activity of the HSC70 chaperone, which dephosphorylates PI(4,5)P2 to PI4P, at the results clathrin coat is disassembled. Internalization mechanism of the virus by micropinocytosis (B). entry of the virus into cells is mediated by the initial attachment of the virus to the heparan sulfate and subsequently, integrins molecules, which is followed by induction of FAK, Src, Ras, and PI3K, signaling molecules. Activation of PI3-K recruits Ub-ligase cCbl which, both monoubiquitinates integrins molecules and leads them into the lipid raft on PM. In lipid rafts virus attached to the ubiquitinated integrins interacts with Ephrin A2 receptor; which results in the recruitment of CIB1 (adaptor protein)-p130Cas (scaffold protein)-Crk (effector protein) molecules to Ephrin A2-integrin -virus complex. CIB1-p130Cas-Crk complex recruits Hrs of ESCRT-0 to the site of macropinocytosis on the PM. Besides activated signaling of Ras and PI3-K induce actin nucleation and polymerization via activation of Cdc42-WASP, Rac1-WAVE complexes, and PAK1. Besides, PIP3 on the PM recruits phospholipase C (PLC), which leads producing of IP3 and diacylglycerol (DAG). DAG, in turn, recruits protein kinase C (PKC) to further promote actin polymerization. After the scission of macropinosomes by CtBP1and/or dynamin (is not shown here) recruitment of Tsg101 by Ephrin A2, c-Cbl, and associated signal molecules, and sequential recruitment of ESCRT I-III complex proteins on the endosome directs macropinosomes to the lysosomal degradation