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

Hong Cai, Ya Chen, Ye Feng, Morad Asadi, Lewis Kaufman, Kyung Lee, Thomas Kehrer, Lisa Miorin, Adolfo Garcia-Sastre, G. Luca Gusella, Leyi Gu, Zhaohui Ni, Shan Mou, John Cijiang He, Weibin Zhou

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Acute kidney injury occurs frequently in COVID-19 patients infected by the coronavirus SARS-CoV-2, and infection of kidney cells by this virus has been reported. However, little is known about the direct impact of the SARS-CoV-2 infection upon the renal tubular cells. We report that SARS-CoV-2 activated signal transducer and activator of transcription 3 (STAT3) signaling and caused cellular injury in the human renal tubular cell line. Mechanistically, the viral protein ORF3A of SARS-CoV-2 augmented both NF-κB and STAT3 signaling and increased the expression of kidney injury molecule 1. SARS-CoV-2 infection or expression of ORF3A alone elevated the protein level of tripartite motif-containing protein 59 (TRIM59), an E3 ubiquitin ligase, which interacts with both ORF3A and STAT3. The excessive TRIM59 in turn dissociated the phosphatase TCPTP from binding to STAT3 and hence inhibited the dephosphorylation of STAT3, leading to persistent STAT3 activation. Consistently, ORF3A induced renal injury in zebrafish and mice. In addition, expression of TRIM59 was elevated in the kidney autopsies of COVID-19 patients with acute kidney injury. Thus, the aberrant activation of STAT3 signaling by TRIM59 plays a significant role in the renal tubular cell injury caused by SARS-CoV-2, which suggests a potential targeted therapy for the renal complications of COVID-19.

Original languageEnglish
Pages (from-to)774-787
Number of pages14
JournalMolecular Therapy
Volume31
Issue number3
DOIs
StatePublished - 1 Mar 2023

Keywords

  • COVID-19
  • NF-κb
  • ORF3A
  • SARS-CoV-2
  • STAT
  • acute kidney injury
  • inflammation
  • phosphorylation
  • renal tubule
  • zebrafish

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