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SARS-CoV-2 viral protein ORF3A injures renal tubules by interacting with TRIM59 to induce STAT3 activation

Hong Cai1, Ya Chen1, Ye Feng2

  • 1Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Jiao Tong University School of Medicine, Shanghai, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|December 16, 2022
PubMed

Insights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection activates signal transducer and activator of transcription 3 (STAT3) signaling, causing kidney injury. This involves the viral protein ORF3A, E3 ligase TRIM59, and persistent STAT3 activation, suggesting therapeutic targets for COVID-19 kidney complications.

Area of Science:

  • Virology
  • Nephrology
  • Molecular Biology

Background:

  • Acute kidney injury (AKI) is a common complication in COVID-19 patients.
  • The direct impact of SARS-CoV-2 on renal tubular cells remains unclear.
  • Understanding viral mechanisms in kidney injury is crucial for effective treatment.

Purpose of the Study:

  • To investigate the direct effects of SARS-CoV-2 on human renal tubular cells.
  • To elucidate the molecular mechanisms underlying SARS-CoV-2-induced kidney injury.
  • To identify potential therapeutic targets for COVID-19-related AKI.

Main Methods:

  • In vitro studies using human renal tubular cell lines.
  • Analysis of viral protein ORF3A interactions with cellular signaling pathways.
  • In vivo studies in zebrafish and mice models.
  • Examination of kidney autopsies from COVID-19 patients.

Main Results:

  • SARS-CoV-2 infection activated STAT3 signaling and caused cellular injury in renal tubular cells.
  • Viral protein ORF3A augmented NF-κB and STAT3 signaling, increasing kidney injury molecule 1.
  • SARS-CoV-2 and ORF3A elevated TRIM59, which inhibited STAT3 dephosphorylation, leading to persistent STAT3 activation.
  • TRIM59 elevation and STAT3 activation were observed in kidney tissues of COVID-19 patients with AKI.

Conclusions:

  • Aberrant STAT3 activation, mediated by TRIM59, plays a key role in SARS-CoV-2-induced renal tubular injury.
  • The SARS-CoV-2 ORF3A protein and elevated TRIM59 are critical in this pathogenic pathway.
  • Targeting the TRIM59-STAT3 axis offers a potential therapeutic strategy for COVID-19-associated kidney disease.
Keywords:
COVID-19NF-κbORF3ASARS-CoV-2STATacute kidney injuryinflammationphosphorylationrenal tubulezebrafish

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