CCHCR1 Interacts Specifically with the E2 Protein of Human Papillomavirus Type 16 on a Surface Overlapping BRD4 Binding

Abstract

The Human Papillomavirus E2 proteins are key regulators of the viral life cycle, whose functions are commonly mediated through protein-protein interactions with the host cell proteome. We identified an interaction between E2 and a cellular protein called CCHCR1, which proved highly specific for the HPV16 genotype, the most prevalent in HPV-associated cancers. Further characterization of the interaction revealed that CCHCR1 binds the N-terminal alpha helices of HPV16 E2 N-terminal domain. On this domain, the CCHCR1 binding interface overlaps that of BRD4, a key mediator of E2 transcriptional activity. Consequently a physical competition occurs between the two proteins for the binding to HPV16 E2, and CCHCR1 interferes with BRD4-mediated enhancement of E2-dependent transcription. In addition, we showed that the interaction with CCHCR1 induced a massive redistribution of HPV16 E2, from a predominantly nuclear to a cytoplasmic localization in dot-like structures, where E2 perfectly co-localizes with CCHCR1. Such a cytoplasmic docking likely interferes with the nuclear functions of HPV16 E2. Upon co-expression of BRD4 and CCHCR1, E2 accumulates both in the nucleus and in the cytoplasm, indicating that for HPV16, both sub-cellular localization and transcriptional functions of E2 may depend on the proportion of both factors within the cell. We provided evidence of a strong induction of the keratinocyte differentiation marker K10 by HPV16 E2, and showed that this activation is compromised by the interaction with CCHCR1. The specific interaction described here could thus impact on the pathogenesis of HPV16. We propose that it could underlie some specific traits of HPV16 infection, such as an enhanced propensity to give rise to lesions evolving toward cancer.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

“…To help identify gene targets, and thus potential therapeutic targets for severe COVID-19, we searched for functional protein-coding variants (missense or predicted loss-of-function) in high LD ( r 2 >0.80) with each variant. We found nine functional variants in six genes ( Supplementary Table 10 ): TMPRSS2 , discussed in greater detail below; IFNAR2 , a cytokine receptor component in the anti-viral type 1 interferon pathway, which is activated by SARS-CoV-2 and is dysregulated in severe COVID-19 cases [25–27]; CCHCR1 , a P-body protein associated with cytoskeletal remodeling and mRNA turnover [28, 29], which can interact with human papillomavirus-16 [30, 31]; TCF19 , a transcription factor associated with hepatitis B [32, 33]; and C6orf15 and PSORS1C1 , two functionally uncharacterized genes in the MHC that are genetically associated with autoimmunity [34]. These data indicate that the risk variants we identified may have functional effects on these six genes.…”

“…To help identify gene targets and thus potential therapeutic targets for severe COVID-19, we searched for functional protein-coding variants (missense or predicted loss-of-function) in high LD (r 2 >0.95) with each variant. We found six functional variants in three genes: two missense variants in IFNAR2, a component of the heterodimeric type-1 interferon receptor; three missense and a stop-gain variant in CCHCR1, a Pbody protein associated with cytoskeletal remodeling and mRNA turnover [22,23], which can interact with human papillomavirus-16 [24,25]; and a missense variant in TCF19, a transcription factor associated with hepatitis B [26,27] (Supplementary Table 9). These data indicate that the risk variants identified in IFNAR2, CCHCR1 and TCF19 may have functional effects on these genes.…”

Intracellular signalling pathways and cytoskeletal functions converge on the psoriasis candidate gene CCHCR1 expressed at P-bodies and centrosomes

“…The P-body localization may also explain some of the putative interactions of CCHCR1 that have been previously identified with such proteins as StAR, RPB3, and viral proteins (Fig. 6 ) [ 11 , 12 , 26 ]. We also compared the gene expression results of the CCHCR1-HEK293 cell lines and psoriatic skin, though the direct comparison of transcriptomes of two completely different biological sample types is unfeasible.…”

Do myeloproliferative neoplasms and multiple myeloma share the same genetic susceptibility loci?

“…Our bioinformatics analysis suggests that this polymorphism is functional, showing a score of 1f in RegulomeDB and that it is an eQTL for the gene CCHCR1 and the noncoding RNA HCG27 in GTEx in whole blood, which represents the closest tissue of interest available in GTEx for MPN. CCHCR1 encodes for a protein with five coiled‐coil alpha‐helical rod domains and is a regulator of cell cycle progression and cell proliferation; its aberrant expression was already associated with other human cancers 28‐31 . For the noncoding RNA HCG27 , no data are available in the literature in relation with cancer.…”

“…KLF2 ‐rs11086029 is in high LD with rs4808485 ( r 2 = 0.98 in CEU), which has a RegulomeDB rank of 1a, corresponding to the highest rank and therefore is very likely to affect protein‐binding sites. In particular, in hematopoietic cell lines, it affects the binding of the protein IKF1, one of the key regulators of maintenance and differentiation 31 …”