IKKε isoform switching governs the immune response against EV71 infection

Abstract

The reciprocal interactions between pathogens and hosts are complicated and profound. A comprehensive understanding of these interactions is essential for developing effective therapies against infectious diseases. Interferon responses induced upon virus infection are critical for establishing host antiviral innate immunity. Here, we provide a molecular mechanism wherein isoform switching of the host IKKε gene, an interferon-associated molecule, leads to alterations in IFN production during EV71 infection. We found that IKKε isoform 2 (IKKε v2) is upregulated while IKKε v1 is downregulated in EV71 infection. IKKε v2 interacts with IRF7 and promotes IRF7 activation through phosphorylation and translocation of IRF7 in the presence of ubiquitin, by which the expression of IFNβ and ISGs is elicited and virus propagation is attenuated. We also identified that IKKε v2 is activated via K63-linked ubiquitination. Our results suggest that host cells induce IKKε isoform switching and result in IFN production against EV71 infection. This finding highlights a gene regulatory mechanism in pathogen-host interactions and provides a potential strategy for establishing host first-line defense against pathogens.

Role of IKKε in the Metabolic Diseases: Physiology, Pathophysiology, and Pharmacology

“…The human IKKε gene is located in the 32.1 region of the long arm of chromosome 1, encoding gene KIAA0151, which is a 3.2-kb DNA fragment ( Peters et al, 2000 ). IKKε gene contains 22 exons and possesses three different isoforms (IKKε v1, IKKε v2, and IKKε v3, as shown in Figure 1 ) ( Chang et al, 2021 ). IKKε v1 is a full-length coding DNA sequence, while IKKε v2 and IKKε v3 lack exon 20 and exon 3, respectively, due to RNA alternative splicing and editing ( Chang et al, 2021 ).…”

“…IKKε gene contains 22 exons and possesses three different isoforms (IKKε v1, IKKε v2, and IKKε v3, as shown in Figure 1 ) ( Chang et al, 2021 ). IKKε v1 is a full-length coding DNA sequence, while IKKε v2 and IKKε v3 lack exon 20 and exon 3, respectively, due to RNA alternative splicing and editing ( Chang et al, 2021 ). The IKKε v2 lacking the helical domain and missing 59 amino acids after amino acid position 644 still maintains its kinase activity ( Chang et al, 2021 ).…”

“…IKKε v1 is a full-length coding DNA sequence, while IKKε v2 and IKKε v3 lack exon 20 and exon 3, respectively, due to RNA alternative splicing and editing ( Chang et al, 2021 ). The IKKε v2 lacking the helical domain and missing 59 amino acids after amino acid position 644 still maintains its kinase activity ( Chang et al, 2021 ). The kinase domain of IKKε v3 is defective, and the kinase activity is lost due to the loss of amino acids at positions 1–85 ( Chang et al, 2021 ).…”

“…The IKKε v2 lacking the helical domain and missing 59 amino acids after amino acid position 644 still maintains its kinase activity ( Chang et al, 2021 ). The kinase domain of IKKε v3 is defective, and the kinase activity is lost due to the loss of amino acids at positions 1–85 ( Chang et al, 2021 ). Mature IKKε is located in the cytoplasm and contains 716 amino acids (IKKε v1).…”

Anti-Inflammatory Functions of Methanol Extract from Malus baccata (L.) Borkh. Leaves and Shoots by Targeting the NF-κB Pathway

“…When microorganisms such as Gram-negative bacteria with lipopolysaccharide (LPS) invade a human body, an innate immune response will be initiated within a few hours. Upon injury and infection, immune cells use pattern recognition receptors (PRRs) to sense exogenous infectious ligands whose molecular structures are broadly shared by pathogens and endogenous molecules that are released from dying and damaged cells [ 1 ]. Toll-like receptors (TLRs), well-characterized members of PRRs, are a membrane-bound protein [ 2 , 3 ].…”