The involvement of minor intron-containing gene-encoded proteins in viral infections

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Oct 6 2022

In a recent study posted to the bioRxiv* preprint server, researchers explored the role of the minor intron-containing gene (MIG)-encoded proteins (MIG-Ps) depending on minor spliceosome-MiG excision to be expressed in infections by pathogenic viruses.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The coronavirus disease 2019 (COVID-19) pandemic uncovered the global unpreparedness to deal with novel emerging viral pathogens, underscoring the need to identify targets for developing broad and effective antiviral therapeutic agents. Minor intron splicing is performed by minor spliceosomes for assured functional protein generation.

Studies have reported that minor spliceosome disruption in human diseases leads to the retention of minor introns in MIG transcripts, resulting in aberrant MIG-P functioning. Particularly, MIGs are present in human genomes for disparate-type biological function execution and are critical for cell survival, leading to considerable conservation.

About the study

In the present study, researchers explored MIG-P involvement in infections caused by viral pathogens.

Host-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PPIs (protein-protein interactions) were investigated. To determine whether MIG-Ps could be enriched significantly, permutation analysis was performed by random sampling of 699 MIG-Ps. Subsequently, the team investigated if MIG-Ps were also leveraged by several other viruses. For comparison, the team investigated if proteins encoded by major spliceosome spliced genes would be enriched.

The researchers determined if MIG-Ps were enriched as host proteins or host-viral factors that don’t mandatorily bind to viral proteins but may facilitate viral replication or inhibit virus replication. Further, they investigated if MIG-Ps were a part of molecular networks downstream of host factors and viral targets.

To determine whether MIG-Ps were enriched in proteins distant from host factors, viral targets, or human PPI networks, perturbation analyses using SARS-CoV-2 as the initial virus of interest were performed. Furthermore, the team investigated whether the viruses leveraged distinctive MIG-P sets or a core of the MIG-P set. The researchers also determined the largest number of viruses that leveraged MIG-P host factors or viral target pairs by cluster analysis.

Genes of 342 cell lines essential for cell survival were obtained, and the transcriptomic profiles in SARS-CoV-2, Middle East respiratory CoV (MERS-CoV), and SARS-CoV-1 infections were examined. The team investigated if MIG-Ps could be targeted by minor spliceosome inhibition. They obtained 114 MIG-Ps from the human embryonic kidney (HEK)-293T cells treated with several small nuclear ribonucleic acid (snRNA) minor spliceosome inhibitors.

The team MIG-P involvement in response to cell function inhibitions to identify mechanisms of viral infections. They also investigated if current antiviral agents could target MIG. In addition, 287 anti-cancer drugs from the cancerDrugsDB database were included in the enrichment analysis. Subsequently, they analyzed the antiviral effects of 29 anti-cancer drugs tested against SARS-CoV-2.

Results

Of host proteins that interacted with those of SARS-CoV-2 (n=332), 20 proteins were found to be MIG-Ps involved in viral replication. Significant MIG-P enrichment was observed among host cell proteins involved in SARS-CoV-2 interactions. Most MIG-Ps showed disparate biological functions used by SARS-CoV-2 for access to host biological mechanisms.

Significant MIG-P enrichment was observed in host-viral PPIs of MERS-CoV, SARS-CoV-1, HIV-1 (human immunodeficiency virus), ZIKV (Zika virus), HPV-1 (human papillomavirus), EBV (Epstein-Barr virus), EBOV (Ebola virus), IAV (influenza A virus), HCV (hepatitis C virus), and HSV-1 (herpes simplex virus 1). Enrichment was greater in host-viral interactomes than in major spliceosome-spliced genes. MIG-Ps molecules were enriched significantly in combined sets of antiviral and proviral host cell factors for all viruses tested except HSV-1 and ZIKV.

The functions executed by MIG-Ps were exploited by viruses to facilitate viral propagation cycles. MIG-Ps were significantly enriched at distances at which proteins interacted directly with viral targets or host factors and were depleted at further distances. MIG-Ps may be critical components of molecular networks leveraged by multiple viruses for replication enhancements, indicating that MIG-Ps were proviral in nature. Viruses were found to shed genes involved in important functions executed by conserved MIG-P molecules.

MIG-Ps, leveraged by many viruses, were significantly critical for survival. Conserved MIG-P host factors and viral targets may provide essential host cell functions that viruses can depend on for secured replication. No MIG-Ps in SARS-CoV-2-host interactomes were expressed differentially. Essential MIG-P viral targets were enriched in highly interactive host factor human protein bins, indicative of concomitant MIG-P targeting as a broad-spectrum antiviral strategy.

Significantly enriched mis-spliced MIG transcripts of responsive MIG-Ps were observed in viral infections, indicating that minor spliceosome inhibition/disruption may interfere with viral replication. Particularly, MIGs were more enriched with host factors or viral targets than disease-based MIG-Ps. Surprisingly, targets of antiviral drugs showed non-responsive MIG-P enrichment.

Conclusion

To conclude, the study findings showed that MIG-P molecules were enriched significantly among cell proteins leveraged by SARS-CoV-2 and other viruses, MIG-Ps were bona fide targets for combating cancers, and that targeting responsive MIGs could be used to develop broad antiviral agents.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.