Abstract
ABSTRACTStress granules (SGs) are dynamic accumulations of stalled preinitiation complexes and translational machinery that assemble under stressful conditions. Sodium selenite (Se) induces the assembly of noncanonical type II SGs that differ in morphology, composition, and mechanism of assembly from canonical SGs. Se inhibits translation initiation by altering the cap-binding activity of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). In this work, we show that human immunodeficiency virus type 1 (HIV-1) Gag is able to block the assembly of type II noncanonical SGs to facilitate continued Gag protein synthesis. We demonstrate that expression of Gag reduces the amount of hypophosphorylated 4EBP1 associated with the 5′ cap potentially through an interaction with its target, eIF4E. These results suggest that the assembly of SGs is an important host antiviral defense that HIV-1 has evolved for inhibition through several distinct mechanisms.
Highlights
Stress granules (SGs) are dynamic accumulations of stalled preinitiation complexes and translational machinery that assemble under stressful conditions
Se induces the assembly of noncanonical type II stress granules (SGs) that contain core SG markers (G3BP1, TIA-1, and TIAR) but lack eIF3 via a mechanism that is dependent upon the production of reactive oxygen species (ROS) [14]
In Se-treated cells transfected with pcDNA3.1, SGs were observed in 95% of cells (Fig. 1C), while only 40% of human immunodeficiency virus type 1 (HIV-1)-expressing cells possessed SGs (Fig. 1B, red arrowhead, and C)
Summary
Stress granules (SGs) are dynamic accumulations of stalled preinitiation complexes and translational machinery that assemble under stressful conditions. Sodium selenite (Se) induces the assembly of noncanonical type II SGs that differ in morphology, composition, and mechanism of assembly from canonical SGs. Se inhibits translation initiation by altering the capbinding activity of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). We demonstrate that expression of Gag reduces the amount of hypophosphorylated 4EBP1 associated with the 5= cap potentially through an interaction with its target, eIF4E These results suggest that the assembly of SGs is an important host antiviral defense that HIV-1 has evolved for inhibition through several distinct mechanisms. We demonstrate that in the face of selenite-induced stress, HIV-1 is able to maintain Gag mRNA translation and to elicit a blockade to selenite-induced stress granule assembly by altering the amount of hypophosphorylated 4EBP1 on the 5= cap. Mammalian target of rapamycin complex 1 (mTORC1) finely tunes translation initiation by phosphorylating its substrate, eIF4E-binding protein 1 (4EBP1). Cell lysates were collected and click chemistry was performed followed by immunoprecipitation (IP) with rabbit anti-p24 antibody
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