Abstract
Despite progress in understanding how virus-induced, NF-κB-dependent pro-inflammatory cytokines are regulated, there are still factors and mechanisms that remain to be explored. We aimed to uncover the relationship between KRAB-zinc finger protein ZNF268a and NF-κB-mediated cytokine production in response to viral infection. To this end, we established a ZNF268a-knockout cell line using a pair of sgRNAs that simultaneously target exon 3 in the coding sequence of the ZNF268 gene in HEK293T. HEK293T cells lacking ZNF268a showed less cytokine expression at the transcription and protein levels in response to Sendai virus/vesicular stomatitis virus (SeV/VSV) infection than wild-type cells. Consistent with HEK293T, knock-down of ZNF268a by siRNAs in THP-1 cells significantly dampened the inflammatory response. Mechanistically, ZNF268a facilitated NF-κB activation by targeting IKKα, helping to maintain the IKK signaling complex and thus enabling proper p65 phosphorylation and nuclear translocation. Taken together, our data suggest that ZNF268a plays a positive role in the regulation of virus-induced pro-inflammatory cytokine production. By interacting with IKKα, ZNF268a promotes NF-κB signal transduction upon viral infection by helping to maintain the association between IKK complex subunits.
Highlights
Inflammation is a pathophysiological immune response that is critical for protecting the host from pathogenic infection [1]
In the case of RNA viruses, such as Sendai virus (SeV) and vesicular stomatitis virus (VSV), once the viral RNA enters the host cell cytosol, retinoic acid-inducible gene I-like receptors (RLRs) family members like RIG-I recognize and bind the viral RNA, activating signaling cascades to induce interferon and pro-inflammatory cytokines that are mainly dependent on the transcription factors IRF3/7 and NF-κB [3]
Using Sendai virus (SeV) and vesicular stomatitis virus (VSV) infection as models, we demonstrated that after infection, ZNF268a binds to IKKα
Summary
Inflammation is a pathophysiological immune response that is critical for protecting the host from pathogenic infection [1]. Cells use various pathogen pattern recognition receptors, such as retinoic acid-inducible gene I-like receptors (RLRs), toll-like receptors, and cyclic. In the case of RNA viruses, such as Sendai virus (SeV) and vesicular stomatitis virus (VSV), once the viral RNA enters the host cell cytosol, RLR family members like RIG-I recognize and bind the viral RNA, activating signaling cascades to induce interferon and pro-inflammatory cytokines that are mainly dependent on the transcription factors IRF3/7 and NF-κB [3]. Less efficient activation of NF-κB may result in insufficient pro-inflammatory cytokine production, leading to chronic infection [4]. In the well-established model of NF-κB activation, various stimuli, including viral infection, activate the pro-inflammatory pathway through different upstream receptors and adaptors, leading to
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