Fig. 7

Activation of PKR by rev/tat pre-mRNA triggers splicing via eIF2α phosphorylation. Activation of PKR occurs through collaborative action of the 3′-terminal TAR element and the pseudoknot (PK) located just upstream in rev/tat pre-mRNA. The helical structures generated by the pseudoknot and by TAR facilitate PKR dimerization and activation. Once activated, PKR catalyzes phosphorylation of eIF2α, which mediates efficient splicing. Activation of PKR is inhibited by mutations in TAR or pseudoknot stem P1, as well as by PKRi and expression of E3L or VP35; phosphorylation of eIF2α by PKR is inhibited by expression of non-phosphorylatable mutant eIF2S51A. The need for PKR activation and eIF2α phosphorylation links HIV-1 mRNA splicing to the integrated stress response