Calcium (Ca2+) is released from the endoplasmic reticulum...

Calcium (Ca2+) is released from the endoplasmic reticulum (ER) lumen to the cytosol through the action of rotavirus A (RV-A) nonstructural protein 4 (NSP4), which localizes to the ER membrane and acts as a viroporin (Tian et al. 1994, Tian et al. 1995: simian RV-A strain SA11 protein expressed in insect Sf9 cells was used; Berkova et al. 2003: SA11 protein expressed in human embryonic kidney cell line HEK293; Díaz et al. 2008: SA11 and bovine RF strain NSP4 proteins expressed in human colorectal carcinoma cell line HT29; Hyser et al. 2010: SA11 protein expressed in monkey kidney cell line MA104 and human HEK293). The same phenomenon is observed with NSP4 of rotavirus B (RV-B) (Tian et al. 1994). NSP4 is therefore an enterotoxin that increases intracellular Ca2+ levels, which drives chloride (Cl-) secretion from infected enterocytes and causes secretory diarrhea early in infection, before any obvious histological damage occurs (reviewed in Ciarlet and Estes 2001). NSP4-mediated increase in cytosolic Ca2+ levels triggers AMPK activation, leading to inhibition of mTOR signaling, which was reported to initiate a rotavirus replication-permissive cellular state characterized by the induction of autophagy (Crawford et al. 2012; Green and Pelkmans 2016), rearrangement of organelles, consumption of lipid stores, reduction in host gene transcription and protein translation, and interference with the cell cycle (Green and Pelkmans 2016).

NSP4-mediated release of Ca2+ from the ER to the cytosol occurs in discrete spikes in both monkey kidney cell line MA104 and human intestinal enteroids (Chang-Graham et al. 2019). In RV-A infected cells, entry of extracellular Ca2+ through the store-operated calcium entry (SOCE) channel ORAI1 likely enables replenishing of ER calcium stores (Chang-Graham et al. 2019).

In the mouse model of rotavirus-induced biliary atresia, where mouse biliary epithelial cells (cholangiocytes) are infected with the simian RV-A strain RRV, VP6-mediated activation of ERK induces increase in cytosolic Ca2+ (Lobeck et al. 2016).