It is shown that PRF functions as a regulatory signal that rewires host translation in favor of viral replication, highlighting PRF as a stress-inducing module that enhances viral replication.
Abstract
Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.
This work provides a conceptual and practical framework for targeting recoding-dependent gene products such as PEG10 in disease and suggests broader applicability of structure-directed ASOs to viral and cellular frameshifting elements.
Ondrej Kostov, Myriam Moreno Swanton, Katie R. Waldon et al.· bioRxiv· 0 citations
DCP2, encoding a major mRNA decapping enzyme, is identified as a previously unrecognized ISR-induced transcript and it is shown that translational induction of DCP2 depends on an overlapping ORF whose conserved 3′ region, corresponding to a ribosome pausing site, acts as a potent inhibitory element.
Many medically important viruses, including HIV-1 and severe acute respiratory syndrome coronavirus 2, utilize programmed -1 ribosomal frameshifting (-1 PRF) to synthesize certain proteins essential for the viral life cycle. Shiftless (SHFL) is an interferon-simulated, zinc finger-containing protein that restricts -1 P...
Shi-Ting He, Yong-Feng Zheng, Ru-Hong Ying et al.· Proceedings of the National...· 0 citations
This study aimed to characterize the mutational and evolutionary patterns of the SVA genome during its transmission within host cells exhibiting enhanced innate immunity, and indicated that the mutant virus was unable to evade host antiviral innate immunity, whereas it significantly enhanced the translational activity...
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The existing mechanistic knowledge about the PTBP1 functions during viral infection is described and the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein is explored.
Human immunodeficiency virus (HIV) encodes four accessory proteins that are essential for virus replication in vivo, primarily through the counteraction of host innate immune defense mechanisms. One of these proteins, Vpr, induces constitutive DNA damage repair (DDR) signaling to drive global epigenetic remodeling and...
Zaddock Williford, Emily Leavitt, Nicholas Saladino et al.· bioRxiv· 0 citations
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