Minding the message: tactics controlling RNA decay, modification, and translation in virus-infected cells.

With their categorical requirement for host ribosomes to translate mRNA, viruses provide a wealth of genetically tractable models to investigate how gene expression is remodeled post-transcriptionally by infection-triggered biological stress. By co-opting and subverting cellular pathways that control mRNA decay, modification, and translation, the global landscape of post-transcriptional processes is swiftly reshaped by virus-encoded factors. Concurrent host cell-intrinsic countermeasures likewise conscript post-transcriptional strategies to mobilize critical innate immune defenses.

Preventing translational inhibition from ribosomal protein insufficiency by a herpes simplex virus-encoded ribosome-associated protein.

In addition to being required for protein synthesis, ribosomes and ribosomal proteins (RPs) also regulate messenger RNA translation in uninfected and virus-infected cells. By individually depleting 85 RPs using RNA interference, we found that overall protein synthesis in uninfected primary fibroblasts was more sensitive to RP depletion than those infected with herpes simplex virus-1 (HSV-1). Although representative RP depletion (uL3, uS4, uL5) inhibited protein synthesis in cells infected with two different DNA viruses (human cytomegalovirus, vaccinia virus), HSV-1-infected cell protein synthesis unexpectedly endured and required a single virus-encoded gene product, VP22.

Targeting the mA RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication.

N-methyladenosine (mA) is an abundant internal RNA modification, influencing transcript fate and function in uninfected and virus-infected cells. Installation of mA by the nuclear RNA methyltransferase METTL3 occurs cotranscriptionally; however, the genomes of some cytoplasmic RNA viruses are also mA-modified. How the cellular mA modification machinery impacts coronavirus replication, which occurs exclusively in the cytoplasm, is unknown.

Remodeling mTORC1 Responsiveness to Amino Acids by the Herpes Simplex Virus UL46 and Us3 Gene Products Supports Replication during Nutrient Insufficiency.

By sensing fundamental parameters, including nutrient availability, activated mechanistic target of rapamycin complex 1 (mTORC1) suppresses catabolic outcomes and promotes anabolic processes needed for herpes simplex virus 1 (HSV-1) productive growth. While the virus-encoded Us3 Ser/Thr kinase is required to activate mTORC1, whether stress associated with amino acid insufficiency impacts mTORC1 activation in infected cells and virus reproduction was unknown. In contrast to uninfected cells, where amino acid withdrawal inhibits mTORC1 activation, we demonstrate that mTORC1 activity is sustained in HSV-1-infected cells during amino acid insufficiency.

Subversion of Host Responses to Energy Insufficiency by Us3 Supports Herpes Simplex Virus 1 Replication during Stress.

Cellular stress responses to energy insufficiency can impact virus reproduction. In particular, activation of the host AMP-activated protein kinase (AMPK) by low energy could limit protein synthesis by inhibiting mTORC1. Although many herpesviruses, including herpes simplex virus 1 (HSV-1), stimulate mTORC1, how HSV-1-infected cells respond to energy availability, a physiological indicator regulating mTORC1, has not been investigated.

Impact of Adenovirus E4-ORF3 Oligomerization and Protein Localization on Cellular Gene Expression.

The Adenovirus E4-ORF3 protein facilitates virus replication through the relocalization of cellular proteins into nuclear inclusions termed tracks. This sequestration event disrupts antiviral properties associated with target proteins. Relocalization of Mre11-Rad50-Nbs1 proteins prevents the DNA damage response from inhibiting Ad replication.

Adenovirus E4-ORF3-dependent relocalization of TIF1α and TIF1γ relies on access to the Coiled-Coil motif.

The adenovirus E4-ORF3 protein promotes viral replication by relocalizing cellular proteins into nuclear track structures, interfering with potential anti-viral activities. E4-ORF3 targets transcriptional intermediary factor 1 alpha (TIF1α), but not homologous TIF1β. Here, we introduce TIF1γ as a novel E4-ORF3-interacting partner.