Model illustrating that the inactivation of SCF^FBXW11 E3 ligase activates PKR and inhibits RVFV infection.

<p>NSs, is expressed early during infection and targets PKR proteosomal degradation by assembling SCF (SKP1-CUL1-F-box)^FBXW11 E3 ligase. The degron sequence in NSs regulates NSs-FBXW11 interaction and is required in the assembly of the SCF^FBXW11-NSs complex. NSs also recruits PKR to the SCF^FBXW11-NS E3 ligase through an alternate binding site. PKR is mostly ubiquitinated by the E2 ubiquitin conjugating enzyme of the SCF^FBXW11 E3 ligase and is subsequently targeted for proteosomal degradation. Disassembly or inactivation of SCF^FBXW11-NSs, which is achieved by the RVFV degron mutant expressing NSs-GE that cannot promote NSs-FBXW11 interaction or by MLN4924 treatment that blocks cullin NEDDylation inhibits PKR degradation. Under these conditions when PKR degradation is blocked, NSs through an as yet not clearly defined mechanism activates PKR. Activated PKR then auto-phosphorylates and subsequently phosphorylates eIF2-α. Accumulation of phosphorylated eIF2-α shuts down ongoing protein synthesis including viral gene translation leading to potent inhibition of RVFV infection.