The bZIP Proteins of Oncogenic Viruses

Abstract

Basic leucine zipper (bZIP) transcription factors (TFs) govern diverse cellular processes and cell fate decisions. The hallmark of the leucine zipper domain is the heptad repeat, with leucine residues at every seventh position in the domain. These leucine residues enable homo- and heterodimerization between ZIP domain α-helices, generating coiled-coil structures that stabilize interactions between adjacent DNA-binding domains and target DNA substrates. Several cancer-causing viruses encode viral bZIP TFs, including human T-cell leukemia virus (HTLV), hepatitis C virus (HCV) and the herpesviruses Marek's disease virus (MDV), Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). Here, we provide a comprehensive review of these viral bZIP TFs and their impact on viral replication, host cell responses and cell fate.

Keywords: Epstein–Barr virus (EBV); Kaposi’s sarcoma-associated herpesvirus (KSHV); Marek’s disease virus (MDV); basic leucine zipper (bZIP); hepatitis C virus (HCV); herpesvirus; human T-cell leukemia virus (HTLV).

Figure 1

Structure of the c-Jun/c-Fos heterodimer. The c-Jun/c-Fos complexes bind DNA as heterodimers. Each bZIP protein contains a leucine zipper (ZIP) and adjacent basic (b) DNA-binding domain that together constitute the bZIP domain. The ZIP domain organizes into heptad repeats with amino acid residues denoted as positions a–g. Hydrophobic interactions (black arrows) between a (blue) and d (red) residues stabilize dimer formation [6]).

Figure 2

Sequence alignment of viral and human bZIPs. Amino acid sequences were obtained from the National Center for Biotechnology Information (NCBI) gene database and from the UniProt Knowledgebase. Colored residues represent consensus (red and gray) or basic (blue) amino acids. The viral bZIPs Zta, K-bZIP, MEQ, HBZ, and NS4B are expressed by the viruses Epstein-Barr virus, Kaposi’s Sarcoma associated herpesvirus, Marek’s disease virus, human T-lymphotropic virus, and hepatitis C virus, respectively. NCBI Accession Numbers: c-Jun NP_002219.1; c-Fos NP_005243.1; C/EBPα AAC50235.1; CHOP NP_001181982.1; CREB1 NP_001358356.1; NFIL3 NP_001276928.1; XBP1s NP_001073007.1; ATF4 NP_001666.2; ATF6α NP_031374.2; ATF6β NP_004372.3; Zta YP_401673.1; K-bZIP AAD21530.1; MEQ AFU65791.1; HBZ BAX35088.1; NS4B PRO_0000037526.

Figure 3

K-bZIP inhibits antiviral innate immune signaling and anti-proliferative signaling. Viral cytosolic dsDNA activates the cGAS/STING pathway, which recruits TBK1 to phosphorylate and activate IRF3. IRF3 transitions to the nucleus to turn on expression of antiviral type 1 IFN genes. The early lytic viral transcription factor K-bZIP prevents IRF3 promoter access to inhibit IFN-β production. K-bZIP inhibits p53 and CDK2 but activates p21 to cause G₀/G₁ cell cycle arrest and prevent apoptosis. K-bZIP also prevents the association of p300/CBP with Smad proteins to inhibit expression of TGF-β-responsive genes in response to TGF-β signaling.

Figure 4

Amino acid similarity of human and chicken bZIP proteins. Amino acid sequences were obtained from the National Center for Biotechnology Information gene database. CREB1 NP_001358356.1 (H) NP_989781.1 (C); ATF1 NP_005162.1 (H) XP_004949774.1 (C); ATF2 NP_001243019.1 (H) NP_990235.1 (C); ATF3 NP_001025458.1 (H) XP_015139364.1 (C); ATF7 NP_001353485.1 (H) XP_025001216.1 (C); NFIL3 NP_001276928.1 (H) NP_989949.1 (C); CHOP NP_001181982.1 (H) XP_015128659.1 (C).

Figure 5

Topology of NS4B in the ER membrane. (A) The AH2 amphipathic helix domain can be positioned on the cytosolic face of the ER, along with the amino-terminal AH1 domain. (B) Insertion of AH2 in the ER membrane translocates the AH1 domain to the ER lumen. It is not yet known how altered NS4B topology affects protein function. TM: transmembrane, AH: amphipathic helix.

Figure 6

NS4B inhibits innate immune signal transduction and interacts with unfolded protein response sensor proteins. Cytoplasmic RIG-I and endosomal TLR3 sense HCV dsRNA and signal through MAVS and TRIF, respectively, leading to the TBK1-dependent phosphorylation and the activation of IRFs that drive IFN-β expression in the nucleus. The viral bZIP and transmembrane protein NS4B prevent the association of MAVS with STING and lead to the enhanced proteasomal degradation of TRIF to inhibit IFN-β production. NS4B also induces ATF6 cleavage and Xbp1 splicing by unknown mechanisms and therefore induces the UPR. NS4B inhibits the XBP1s-dependent expression of ER-associated degradation genes.