Interaction of NCOR/SMRT Repressor Complexes with Papillomavirus E8^E2C Proteins Inhibits Viral Replication

Marcel Dreer, Jasmin Fertey, Saskia van de Poel, Elke Straub, Johannes Madlung, Boris Macek, Thomas Iftner, Frank Stubenrauch, Paul Francis Lambert
<span title="2016-04-11">2016</span> <i title="Public Library of Science (PLoS)"> <a target="_blank" rel="noopener" href="" style="color: black;">PLoS Pathogens</a> </i> &nbsp;
Infections with high-risk human papillomaviruses (HR-HPV) such as HPV16 and 31 can lead to ano-genital and oropharyngeal cancers and HPV types from the beta genus have been implicated in the development of non-melanoma skin cancer. HPV replicate as nuclear extrachromosomal plasmids at low copy numbers in undifferentiated cells. HPV16 and 31 mutants have indicated that these viruses express an E8^E2C protein which negatively regulates genome replication. E8^E2C shares the DNA-binding and
more &raquo; ... tion domain (E2C) with the essential viral replication activator E2 and the E8 domain replaces the replication/transcription activation domain of E2. The HR-HPV E8 domain is required for inhibiting viral transcription and the replication of the viral origin mediated by viral E1 and E2 proteins. We show now that E8^E2C also limits replication of HPV1, a mu-PV and HPV8, a beta-PV, in normal human keratinocytes. Proteomic analyses identified all NCoR/SMRT corepressor complex components (HDAC3, GPS2, NCoR, SMRT, TBL1 and TBLR1) as co-precipitating host cell proteins for HPV16 and 31 E8^E2C proteins. Co-immunoprecipitation and co-localization experiments revealed that NCoR/SMRT components interact with HPV1, 8, 16 and 31 E8^E2C proteins in an E8-dependent manner. SiRNA knock-down experiments confirm that NCoR/SMRT components are critical for both the inhibition of transcription and HPV origin replication by E8^E2C proteins. Furthermore, a dominant-negative NCoR fragment activates transcription and replication only from HPV16 and 31 wt but not from mutant genomes encoding NCoR/SMRT-binding deficient E8^E2C proteins. In summary, our data suggest that the repressive function of E8^E2C is highly conserved among HPV and that it is mediated by an E8-dependent interaction with NCoR/SMRT complexes. Our data also indicate for the first time that NCoR/SMRT complexes not only are involved in inhibiting cellular and viral transcription but also in controlling the replication of HPV origins. Human papillomaviruses (HPV) have been shown to cause ano-genital and oropharyngeal cancers and have been also implicated in non-melanoma skin cancer. HPV have a twostage replication cycle: in undifferentiated keratinocytes only a low level of genome replication without virus production can be observed whereas in differentiated keratinocytes high-level genome replication and virus production takes place. Previous studies have suggested that some HPV encode an E8^E2C protein that limits genome replication in undifferentiated cells. We now demonstrate that E8^E2C proteins from phylogenetically diverse HPV types interact with NCoR/SMRT corepressor complexes to limit viral transcription and genome replication. While NCoR/SMRT complexes are known to mediate the transcription repression functions of a wide variety of host transcription factors, this is the first evidence that NCoR/SMRT proteins also are involved in the repression of the replication of viral origins. NCoR/SMRT Corepressor Inhibits HPV Replication PLOS Pathogens |
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="">doi:10.1371/journal.ppat.1005556</a> <a target="_blank" rel="external noopener" href="">pmid:27064408</a> <a target="_blank" rel="external noopener" href="">pmcid:PMC4827801</a> <a target="_blank" rel="external noopener" href="">fatcat:ryrltpxbwjcfvebjbfucicdupa</a> </span>
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