Poxviruses are double-stranded DNA viruses that infect insects and a variety of vertebrate species. The large genomes of poxviruses contain numerous genes that allow these viruses to successfully establish infection, including those that help evade the host immune response and prevent cell death. Ankyrin-repeat (ANKR)/F-box proteins are almost exclusively found in poxviruses, and they function as substrate adapters for Skp1-Cullin-1-F-box protein (SCF) multi-subunit E3 ubiquitin (Ub)-ligases. In this regard, they use their C-terminal F-box domain to bind Skp1, Cullin-1, and Roc1 to recruit cellular E2 enzymes to facilitate the ubiquitylation, and subsequent proteasomal degradation, of proteins bound to their N-terminal ANKRs. However, these proteins do not just function as substrate adapters as they also have Ub-independent activities. In this review, we examine both Ub-dependent and -independent activities of ANKR/F-box proteins and discuss how poxviruses use these proteins to counteract the host innate immune response, uncoat their genome, replicate, block cell death, and influence transcription. Finally, we consider important outstanding questions that need to be answered in order to better understand the function of this versatile protein family.

Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is a T cell lymphoma which features translocations or inversion involving the ALK tyrosine kinase gene, and results in oncogenic fusion proteins (e.g. NPM-ALK). The elevated expression and/or activation of activator protein-1 (AP-1) transcription factors, c-Jun and JunB, is another molecular feature of ALK+ ALCL. c-Jun/JunB transcriptional targets are important in the pathobiology of this lymphoma, and several are also therapeutic targets. To better understand c-Jun/JunB function in ALK+ ALCL, we performed chromatin immunoprecipitation–sequencing experiments in the Karpas 299 ALK+ ALCL cell line to comprehensively identify sites bound by these transcription factors. We identified 13,083 c-Jun and 40,369 JunB binding sites, and ~60% of sites bound by c-Jun were shared with JunB. Many sites were associated with genes known or predicted to be important in the pathogenesis of ALK+ ALCL. Pathway enrichment analysis of genes associated with both c-Jun and JunB binding sites revealed a significant over-representation for pathways associated with cancer and cell signalling. Furthermore, we identified several c-Jun and JunB binding sites associated with the NIBAN2 / FAM129B gene. FAM129B is a PH domain-containing phosphoprotein that promotes proliferation in multiple cell types. However, while we found that FAM129B knock-down resulted in modest cell cycle alteration in most ALK+ ALCL cell lines, this did not appear to result in a significant proliferation defect. Finally, we found that inhibition of NPM-ALK and MEK/Erk signalling altered FAM129B electrophoretic mobility and decreased phosphorylation of FAM129B on serine residues known to be Erk phosphosites. In summary, this study is the first to globally profile sites bound by c-Jun/JunB in ALK+ ALCL. It reveals novel putative targets for these transcription factors in ALK+ ALCL, and identifies FAM129B as a novel phosphoprotein downstream of NPM-ALK signalling.