Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense

Abstract

The Nrf2/Keap1 axis plays a complex role in viral susceptibility, virus-associated inflammation and immune regulation in host cells. However, whether or how the Nrf2/Keap1 axis is involved in the interactions between equine lentiviruses and their hosts remains unclear. Here, we demonstrate that the Nrf2/Keap1 axis was activated during EIAV infection. Mechanistically, EIAV-Rev competitively binds to Keap1 and releases Nrf2 from Keap1-mediated repression, leading to the accumulation of Nrf2 in the nucleus and promoting Nrf2 responsive genes transcription. Subsequently, we demonstrated that the Nrf2/Keap1 axis represses EIAV replication via two independent molecular mechanisms: directly increasing antioxidant enzymes to promote effective cellular resistance against EIAV infection, and repression of Rev-mediated RNA transport through direct interaction between Keap1 and Rev. Together, these data suggest that activation of the Nrf2/Keap1 axis mediates a passive defensive response to combat EIAV infection. The Nrf2/Keap1 axis could be a potential target for developing strategies for combating EIAV infection.

A Novel, Fully Spliced, Accessory Gene in Equine Lentivirus with Distinct Rev-Responsive Element

“…1D ). To further confirm the production of mat transcript from EIAV, we aligned mat-, s4-, s5-, and tat/rev-specific sequences with transcriptomic data from EIAV-infected eMDMs obtained by RNA-seq ( 35 ) and found mat-specific reads and other EIAV-specific reads ( Fig. 1E ) that were not found in uninfected eMDMs.…”

“…One or two representative samples without reverse transcription were used as controls in each PCR analysis to ensure the elimination of transfected plasmid DNA. The distribution ratio of nuclear and cytoplasmic mat mRNA (GFP, mat-exon1, or gag mRNA) from the same sample was calculated essentially as described previously ( 35 , 62 ).…”

MHC class Ia molecules facilitate MCK2-dependent MCMV infection of macrophages and virus dissemination to the salivary gland

“…Protein disulfide isomerase associated 3 is a chaperone protein encoded by Pdia3 that prevents protein aggregation and is upregulated upon influenza inflammation in lung cells (Chamberlain et al, 2019). Finally, Keap1 encodes for an inhibitor of the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor important for the suppression of oxidative stress induced by viral infection (Wang et al, 2022). Altogether, these data implied that the cell-surface expressed MHC-I/B2m complex and CD81 serve for MCK2-mediated MCMV entry into the cells.…”

Identification of a Novel Post-transcriptional Transactivator from the Equine Infectious Anemia Virus

“…1E ), suggesting that grev transcript is derived from EIAV-specific mRNA and not EIAV proviral DNA. In addition, the abundance of viral mRNA arising from the EIAV genome was analyzed based on our previously published RNA-seq data from eMDMs infected with EIAV DLV121 ( 37 ). Using reads with tat/rev-specific splicing sites as controls, we found reads with grev -specific splicing sites in the eMDMs infected with EIAV, but not in the uninfected eMDMs ( Fig.…”

“…The NES of Rev is located at the N-terminal region of its second exon, containing a number of hydrophobic residues and three leucines ( 31 , 51 ). Lentiviral Rev performs nuclear export activity dependent on its own multimerization ( 23 , 29 , 37 , 40 ). Both this and other studies ( 31 ) found that EIAV Rev, like HIV-1 Rev, also exists in multimeric forms in cells.…”