An eIF3d-dependent switch regulates HCMV replication by remodeling the infected cell translation landscape to mimic chronic ER stress

eIF3d: A driver of noncanonical cap–dependent translation of specific mRNAs and a trigger of biological/pathological processes

“…In a recent study, it was found that the eIF3d protein level increased in response to human cytomegalovirus (HCMV) infection, whereas its mRNA level remained unchanged ( 87 ). Interestingly, silencing eIF3d expression using siRNA inhibited HCMV reproduction and reduced polyribosome abundance and virus protein accumulation.…”

Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis

“…While the mTORC1/4E-BP1 axis permits eIF4E-mediated cap-dependent mRNA translation under normal growth conditions (48), various stresses inhibit mTORC1 activity, resulting in hypophosphorylated 4E-BPs that sequester eIF4E and thereby reduce translation initiation (49,50). However, in the absence of functional eIF4F, alternative mechanisms, such as those including eIF3d (a subunit of the eIF3 complex with cap-binding activity) (17)(18)(19)(20) or the m 6 A-pathway, which requires methyltransferase-like 3 (METTL3) (51), ATP Binding Cassette Subfamily F Member 1 (ABCF1) (52), or YTH N6-Methyladenosine RNA Binding Protein F1 (YTHDF1) (53), have been proposed to be for translation initiation. We found that Eer1-induced paraptosis was markedly inhibited by the knockdown of eIF3d but not that of eIF4E, METTL3, ABCF1, or YTHDF1 (Fig.…”

“…In this process, the activating transcription factor 4 (ATF4)/DNA damage-inducible transcript 4 (DDIT4) axis and mechanistic target of rapamycin complex 2 (mTORC2)/Akt signals critically contribute to translational recovery and consequent proteotoxic stress. Eukaryotic translation initiation factor 3 subunit D (eIF3d), an alternative cap-recognition subunit that can mediate the 40S loading independent of eukaryotic translation initiation factor 4E (eIF4E) (17), helps enable protein synthesis to adapt to various stresses (18)(19)(20). We report that eIF3d mediates translational recovery in cancer cells exposed to VCP inhibition-mediated proteotoxic stress.…”

CCR4‐NOT differentially controls host versus virus poly(a)‐tail length and regulates HCMV infection

“…Infection with HCMV results, rather than shut‐off, in an overall stimulation of protein synthesis with viral proteins produced alongside those of the host cell (McKinney et al , 2014). To engineer this increase in protein synthetic capacity, multiple layers of translational control are manipulated and the abundance of many translation factors, including cytoplasmic poly(A)‐binding protein 1 (PABPC1), as well as ribosomal proteins is upregulated (Walsh et al , 2005; McKinney et al , 2012; Tirosh et al , 2015; Bianco & Mohr, 2019; Thompson et al , 2022). Host gene expression is nevertheless distinctly manipulated by HCMV, and significant changes in host protein abundances have been comprehensively characterized in lytically infected fibroblasts (Weekes et al , 2014).…”

“…Host gene expression is nevertheless distinctly manipulated by HCMV, and significant changes in host protein abundances have been comprehensively characterized in lytically infected fibroblasts (Weekes et al , 2014). Changes to RNA abundance accounts for much of this manipulation of host gene expression, with translational regulation acting on specific sets of host genes (McKinney et al , 2014; Tirosh et al , 2015; Thompson et al , 2022).…”