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Analysis of Translation Initiation During Stress Conditions by Polysome Profiling

Analysis of Translation Initiation During Stress Conditions by Polysome Profiling

Published on: May 19, 2014

Influenza a virus host shutoff disables antiviral stress-induced translation arrest

Denys A Khaperskyy¹, Mohamed M Emara², Benjamin P Johnston¹

¹Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.

|July 11, 2014

Abstract:

Influenza A virus (IAV) polymerase complexes function in the nucleus of infected cells, generating mRNAs that bear 5' caps and poly(A) tails, and which are exported to the cytoplasm and translated by host machinery. Host antiviral defences include mechanisms that detect the stress of virus infection and arrest cap-dependent mRNA translation, which normally results in the formation of cytoplasmic aggregates of translationally stalled mRNA-protein complexes known as stress granules (SGs). It remains unclear how IAV ensures preferential translation of viral gene products while evading stress-induced translation arrest. Here, we demonstrate that at early stages of infection both viral and host mRNAs are sensitive to drug-induced translation arrest and SG formation. By contrast, at later stages of infection, IAV becomes partially resistant to stress-induced translation arrest, thereby maintaining ongoing translation of viral gene products. To this end, the virus deploys multiple proteins that block stress-induced SG formation: 1) non-structural protein 1 (NS1) inactivates the antiviral double-stranded RNA (dsRNA)-activated kinase PKR, thereby preventing eIF2α phosphorylation and SG formation; 2) nucleoprotein (NP) inhibits SG formation without affecting eIF2α phosphorylation; 3) host-shutoff protein polymerase-acidic protein-X (PA-X) strongly inhibits SG formation concomitant with dramatic depletion of cytoplasmic poly(A) RNA and nuclear accumulation of poly(A)-binding protein. Recombinant viruses with disrupted PA-X host shutoff function fail to effectively inhibit stress-induced SG formation. The existence of three distinct mechanisms of IAV-mediated SG blockade reveals the magnitude of the threat of stress-induced translation arrest during viral replication.

Insights

Influenza A virus evades host defenses by blocking stress granule formation. Multiple viral proteins, including NS1, NP, and PA-X, prevent the arrest of viral mRNA translation during infection.

Area of Science:

Virology
Molecular Biology
Cellular Stress Response

Background:

Influenza A virus (IAV) replicates in the host cell nucleus, producing viral mRNAs for translation.
Host cells possess antiviral mechanisms, like stress granule (SG) formation, that arrest mRNA translation during viral infection.
IAV's strategy for preferential viral gene translation amidst host stress responses remains poorly understood.

Purpose of the Study:

To investigate how IAV maintains viral protein synthesis by evading host-induced translation arrest and SG formation.
To identify the viral factors and mechanisms involved in blocking stress-induced SG formation during IAV infection.

Main Methods:

Analysis of viral and host mRNA translation sensitivity to drug-induced stress and SG formation at different infection stages.
Investigating the role of IAV proteins NS1, NP, and PA-X in inhibiting SG formation.
Utilizing recombinant IAV with disrupted PA-X function to assess its impact on SG inhibition.

Main Results:

At early infection stages, both viral and host mRNAs are sensitive to translation arrest and SG formation.
At later stages, IAV develops partial resistance to stress-induced translation arrest, ensuring viral gene product synthesis.
IAV employs three distinct mechanisms to block SG formation: NS1 (inactivates PKR), NP (inhibits SG formation independently of eIF2α phosphorylation), and PA-X (inhibits SG formation with poly(A) RNA depletion).
Disruption of PA-X host shutoff function impairs the virus's ability to inhibit stress-induced SG formation.

Conclusions:

IAV utilizes multiple viral proteins (NS1, NP, PA-X) to counteract host-induced stress granule formation and translation arrest.
These mechanisms are crucial for maintaining viral protein synthesis and replication, highlighting the significance of blocking host antiviral responses.
The identified viral strategies underscore the substantial threat posed by stress-induced translation arrest to IAV replication.

Read full analysis

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