SARS-CoV-2 spike protein and messenger ribonucleic acid found to translocate into the nucleus

In a recent study posted to the bioRxiv* preprint server, researchers reported severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) spike (S) protein and S messenger ribonucleic acid (mRNA) nuclear co-translocation as a novel feature of SARS-CoV-2 pathogenesis.

Study: Nuclear translocation of spike mRNA and protein is a novel pathogenic feature of SARS-CoV-2. Image Credit: Naeblys/Shutterstock
Study: Nuclear translocation of spike mRNA and protein is a novel pathogenic feature of SARS-CoV-2. Image Credit: Naeblys/Shutterstock

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Background

The causative organism of coronavirus disease 2019 (COVID-19), SARS-CoV-2, has caused severe pathophysiological alterations among elder and vulnerable individuals and is reported to have greater transmissibility than severe acute respiratory syndrome coronavirus (SARS-CoV) or Middle East respiratory syndrome CoV (MERS-CoV).

SARS-CoV-2 S protein has been documented as a key factor for SARS-CoV-2 pathogenicity due to its broad tropism for the human angiotensin-converting enzyme 2 (hACE2) receptor.

Studies have investigated SARS-CoV-2 protein subcellular localization in vitro; however, comprehensive data on the S glycoprotein needs are limited and require further investigation.

About the study

In the present study, researchers explored S and S mRNA nuclear translocation as underlying mechanisms of SARS-CoV-2 pathogenicity.

Primary normal human bronchial epithelial (NHBE) cells were obtained from healthy non-smoker individuals and chronic obstructive pulmonary disease (COPD) patients to form a pseudostratified bronchial airway epithelium. The airway cells were infected with the SARS-CoV-2 USA/WA-CDC-WA1/2020 strain, SARS-CoV Urbani strain, and MERS-CoV for in vitro experiments.

The team investigated whether SARS-CoV-2 S translocated into the SARS-CoV-2-infected airway epithelial cell nucleus and colocalized with S mRNA. The cells were subjected to immunohistochemistry (IHC) analysis and were examined by confocal microscopy (CFM). Immunofluorescence analysis was performed for SARS-CoV-2 protein and S mRNA detection.

S sequences of both the viruses were aligned by the multiple sequence alignment (MSA) technique to determine whether the SARS-CoV-2 isolate has multiple novel sequence insertions (SIs) in S compared to the Urbani strain of SARS-CoV. Further, SARS-CoV-2 S was analyzed using in silico analysis to investigate whether S resembled or constituted protein motifs such as a nuclear localization signal (NLS) and to study the interactions between SARS-CoV-2 RNA and the S and nucleocapsid (N) proteins.

NLS estimation was performed for several pathogenic CoV S proteins. The team investigated whether the “RRAR” polybasic site could be an NLS motif and whether the NLS motif was functional concerning the polybasic RRAR site at the boundary between S subunits 1 (S1) and 2 (S2).

Results

Only SARS-CoV-2 S contained a functional NLS motif “PRRARSV” of pat7-type at the S1/S2 boundary due to the presence of the novel ‘NSPR’ SI and drove nuclear translocation of S protein (and S mRNA) in the airway epithelial cells infected by SARS-CoV-2. SARS-CoV-2 S mRNA was found to be nuclear (<10%) and abundant (~90%) in the cytoplasm, indicative of mRNA transition. In less than one percent of cases, complete translocation of S protein mRNA was observed.

Intracellular S and S protein mRNA distribution was observed, indicative of nuclear translocation, involving the outer surface and the inside of the nucleus. S and S protein mRNA colocalized and formed a protein-mRNA complex in the infected cells, 85% of which was detected outside the nucleus. The N proteins of MERS-CoV, SARS-CoV, and SARS-CoV-2 demonstrated nuclear translocation.

S translocated into the nucleus (25%) of the airway cells through the cytoplasmic endoplasmic reticulum (ER)-Golgi apparatus pathway, and 15% of the S protein was detected at the nuclear surface, indicative of a transitionary stage in protein translocation. Of note, the nuclear translocation of S mRNA located on the nucleus's surface was associated with and assisted by SARS-CoV-2 S. In contrast, S mRNA present in the cytoplasmic did not show such associations. NLS-facilitated translocations into the nucleus were observed for MERS-CoV, SARS-CoV, and SARS-CoV-2.

Conclusions

Overall, the study findings showed nuclear translocation and co-localization of the S glycoprotein and S mRNA, a novel mechanism of SARS-CoV-2 pathogenesis. Further, the S glycoprotein mRNA nuclear translocation was facilitated by the S protein due to the presence of the functional pat7 NLS “PRRARSV” motif in SARS-CoV-2 S.

The findings could aid the development of effective S-targeted agents to widen the therapeutic landscape of COVID-19.

The novel SARS-CoV-2 nuclear translocation indicates that S protein surface expression may be reduced, but its impact on host immune recognition needs to be determined. S and S mRNA colocalization indicate that the SARS-CoV-2 S may contain an RNA-binding motif and therefore, must be investigated further.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Journal references:

Article Revisions

  • May 15 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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