scholarly journals KRAB-Zinc Finger Protein ZNF268a Deficiency Attenuates the Virus-Induced Pro-Inflammatory Response by Preventing IKK Complex Assembly

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1604 ◽  
Author(s):  
Yi Liu ◽  
Wei Yin ◽  
Jingwen Wang ◽  
Yucong Lei ◽  
Guihong Sun ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Viral Infection ◽  
Zinc Finger ◽  
Cytokine Production ◽  
Zinc Finger Protein ◽  
Nuclear Translocation ◽  
Sendai Virus ◽  
Positive Role ◽  
Finger Protein ◽  
Ikk Complex

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.

scholarly journals The Zinc Finger Protein A20 Inhibits TNF-induced NF-κB–dependent Gene Expression by Interfering with an RIP- or TRAF2-mediated Transactivation Signal and Directly Binds to a Novel NF-κB–inhibiting Protein ABIN

1999 ◽  
Vol 145 (7) ◽  
pp. 1471-1482 ◽  
Author(s):  
Karen Heyninck ◽  
Dirk De Valck ◽  
Wim Vanden Berghe ◽  
Wim Van Criekinge ◽  
Roland Contreras ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Nuclear Translocation ◽  
Tnf Receptor ◽  
Cell Leukemia Virus Type ◽  
Finger Protein ◽  
Iκb Kinase ◽  
Human T Cell ◽  
Inhibiting Protein

The zinc finger protein A20 is a tumor necrosis factor (TNF)– and interleukin 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kappa B (NF-κB)–dependent gene expression. However, the molecular mechanism by which A20 exerts this effect is still unclear. We show that A20 does not inhibit TNF- induced nuclear translocation and DNA binding of NF-κB, although it completely prevents the TNF- induced activation of an NF-κB–dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage–colony stimulating factor gene expression. Moreover, NF-κB activation induced by overexpression of the TNF receptor–associated proteins TNF receptor–associated death domain protein (TRADD), receptor interacting protein (RIP), and TNF recep- tor–associated factor 2 (TRAF2) was also inhibited by expression of A20, whereas NF-κB activation induced by overexpression of NF-κB–inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-κB–dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK–IκB kinase pathway and that is specifically involved in the transactivation of NF-κB. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-κB inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-κB inhibiting protein, ABIN.

scholarly journals Zinc Finger Protein Gfi1 Controls the Endotoxin-Mediated Toll-Like Receptor Inflammatory Response by Antagonizing NF-κB p65

2010 ◽  
Vol 30 (16) ◽  
pp. 3929-3942 ◽  
Author(s):  
Ehssan Sharif-Askari ◽  
Lothar Vassen ◽  
Christian Kosan ◽  
Cyrus Khandanpour ◽  
Marie-Claude Gaudreau ◽  
...  
Keyword(s):  
Septic Shock ◽  
Zinc Finger ◽  
Transcriptional Activation ◽  
Zinc Finger Protein ◽  
Nuclear Translocation ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Finger Protein ◽  
Tnf Α

ABSTRACT Endotoxin (bacterial lipopolysaccharide [LPS]) causes fatal septic shock via the Toll-like receptor 4 (TLR-4) protein present on innate immunity effector cells, which activates nuclear factor kappa B (NF-κB), inducing proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α). An early step in this process involves nuclear sequestration of the p65-RelA NF-κB subunit, enabling transcriptional activation of target inflammatory cytokine genes. Here, we analyzed the role of the nuclear zinc finger protein Gfi1 in the TLR response using primary bone marrow-derived macrophages. We show that upon LPS stimulation, expression of Gfi1 is induced with kinetics similar to those of nuclear translocation of p65 and that Gfi1 interacts with p65 and inhibits p65-mediated transcriptional transactivation by interfering with p65 binding to target gene promoter DNA. Gfi1-deficient macrophages show abnormally high mRNA levels of the TNF-α gene and many other p65 target genes and a higher rate of TNF promoter occupancy by p65 than wild-type cells after LPS stimulation, suggesting that Gfi1 functions as an antagonist of NF-κB activity at the level of promoter binding. Our findings identify a new function of Gfi1 as a general negative regulator of the endotoxin-initiated innate immune responses, including septic shock and possibly other severe inflammatory diseases.

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