The rotavirus A (RV-A) virions, known as triple-layer par...

The rotavirus A (RV-A) virions, known as triple-layer particles (TLPs), interact with the lumenal surface of enterocytes via their VP4 spikes that consist of trypsin cleaved VP4 fragments, VP8* and VP5*, and VP7, which forms the smooth surface of the TLP (reviewed in Desselberger 2014, Crawford et al. 2017, Suzuki 2019). The infectious RV-A TLP interacts by its VP4 spikes with cellular receptors that contain sialic acid (SA) in terminal or sub-terminal positions (reviewed in Desselberger 2014). The attachment is mediated by the VP8* subunit of VP4, so that a shallow groove of the VP8* surface interacts with SAs on cellular glycans (reviewed in Desselberger 2014). Certain RV-A strains bind to non-SA containing histo-blood group antigens (HBGA) that contain the GalBeta1–4GlcNAc motif (reviewed in Desselberger 2014, Crawford et al. 2017, Suzuki 2019). Additional cell surface molecules associated with lipid rafts can act as post-attachment co-receptors (reviewed in Desselberger 2014, Crawford et al. 2017, Suzuki 2019). Known co-receptors include integrin dimers ITGA2:ITGB1, ITGAV:ITGB3, ITGAX:ITGB2, and ITGA4:ITGB1, as well as the heat shock cognate protein HSPA8 (also known as HSC70), which bind to integrin ligand motifs on VP5* subunit of VP4 or on VP7 (reviewed in Desselberger 2014, Crawford et al. 2017, Suzuki 2019).

After RV-A TLPs attach to host cell receptors, they can be internalized via clathrin-dependent or clathrin-independent receptor-mediated endocytosis, depending on the rotavirus strain (reviewed in Arias et al. 2015, Suzuki 2019). Endocytosed rotavirus TLPs travel through different endosomal compartments, such as early endosomes, maturing endosomes and late endosomes, losing their outer layer and being released into the cytosol as transcriptionally active double-layer particles (DLPs) (reviewed in Arias et al. 2015, Suzuki 2019). The initial uncoating is thought to be related to the decrease of calcium in endosomes, which promotes the release of VP7, while VP4 and its cleavage product VP5* are believed to undergo a conformational rearrangement which enables interaction of their hydrophobic domains with the endosomal membrane, resulting in disruption of the outer layer (reviewed in Desselberger 2014, Arias et al. 2015, Suzuki 2019). Activation of host PI3K/AKT and MEK/ERK signaling through interaction of the outer capsid proteins with host cell receptors during viral attachment and entry may facilitate viral uncoating by driving endosomal acidification (Soliman et al. 2018). The heat shock protein HSP90 promotes RV-A infection by facilitating the activation of the AKT signaling pathway upon viral attachment to the host cells (Dutta et al. 2009).