Figure 6

Summary of the UPR pathway in rotavirus infected cells. 6A: 1A) Under ER stress, GRP78 is uncoupled from UPR sensors. 2A) ATF6 translocates to the Golgi where it is cleaved and transported to the nucleus. 3A) PERK is auto-phosphorylated. P-PERK phosphorylates eIF2α, stimulating the expression of ATF4, a transcription factor that is transported to the nucleus. 4A) IRE1 is auto-phosphorylated leading to splicing of XBP1 mRNA. XBP1 is transported to the nucleus. Phosphorylation of IRE1 may trigger autophagy via the JNK pathway. 5A) ATF6, ATF4 and XBP1 are bind to DNA upstream of UPR Element (UPRE) and ER Stress Element (ESRE) that triggers over-expression of other transcription factors and ER resident chaperones. Stress effectors proteins CHOP, GADD34, and Nrf2 may induce activation of other metabolic pathways, stress response or apoptosis. 6B: 1B) Viroplasms begin to assemble 3 hpi and interaction with the ER may induce morphological changes and rearrangement of the ER membrane. 2B) Chaperones are condensed around viroplasms. 3B) ATF6 is immobilized in the ER-viroplasms complex preventing its transport to the nucleus. 4B) p-PERK signal is sequestered within the viroplasms. 5B) XBP1 is expressed and directed to the ER-viroplasm complex. 6B) UPR effector proteins are expressed but their nuclear transport is blocked and instead they are sequestered in or around viroplasms.