Np9, a cellular protein of retroviral ancestry restricted to human, chimpanzee and gorilla, binds and regulates ubiquitin ligase MDM2

Abstract

Humans and primates are long-lived animals with long reproductive phases. One factor that appears to contribute to longevity and fertility in humans, as well as to cancer-free survival, is the transcription factor and tumor suppressor p53, controlled by its main negative regulator MDM2. However, p53 and MDM2 homologs are found throughout the metazoan kingdom from Trichoplacidae to Hominidae. Therefore the question arises, if p53/MDM2 contributes to the shaping of primate features, then through which mechanisms. Previous findings have indicated that the appearances of novel p53-regulated genes and wild-type p53 variants during primate evolution are important in this context. Here, we report on another mechanism of potential relevance. Human endogenous retrovirus K subgroup HML-2 (HERV-K(HML-2)) type 1 proviral sequences were formed in the genomes of the predecessors of contemporary Hominoidea and can be identified in the genomes of Nomascus leucogenys (gibbon) up to Homo sapiens. We previously reported on an alternative splicing event in HERV-K(HML-2) type 1 proviruses that can give rise to nuclear protein of 9 kDa (Np9). We document here the evolution of Np9-coding capacity in human, chimpanzee and gorilla, and show that the C-terminal half of Np9 binds directly to MDM2, through a domain of MDM2 that is known to be contacted by various cellular proteins in response to stress. Np9 can inhibit the MDM2 ubiquitin ligase activity toward p53 in the cell nucleus, and can support the transactivation of genes by p53. Our findings point to the possibility that endogenous retrovirus protein Np9 contributes to the regulation of the p53-MDM2 pathway specifically in humans, chimpanzees and gorillas.

Targeting endogenous retrovirus gene transcription in human cancers

“…HERV expression is very well-documented in testicular germ cell tumoursgerm cell tumour cell lines have been shown to express HK2 non-infectious particles [32] , [33] , [34] . HERV-K has also been shown to be overexpressed at specific stages of early embryonic development [7] , [9] , [11] , which we also observed using our novel method. Germ cell tumours also share with early embryonic cells similar traits of embryonic stem cell identity, such as the upregulation of the pluripotency factors Oct3/4, Nanog, and Sox2 [35] .…”

“…The Np9-Rec-PLZF interaction results in the de-repression of the c-myc proto-oncogene, c-Myc overexpression, altered expression of genes regulated by c-Myc, and increased cell survival and proliferation [2] . Np9 protein is also reported to bind and regulate ubiquitin ligase MDM2, which represses the activity of p53 tumour suppressor [9] . Transcripts of np9 and rec are also found in human embryonic stem cells and human induced pluripotent stem cell lines, and are associated with maintenance of pluripotency [10] , [11] .…”

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

“…4E). We also observed an upregulation of the np9 and rec alternative transcripts, which encode for proteins with oncogenic potential and promoting expression of the IFITM1 antiviral factor (21)(22)(23)(24)(25). As well, KZFP-depleted iN were characterized by the upregulation of IFNγ and ISGs such as TNF, IFITMs, APOBEC3B, IRF1, IFIH1 (a.k.a.…”

HERV-K HML-2 transcription in diverse cancers is related with cancer stem cell and epithelial-mesenchymal transition markers

“…Previous studies have also shown that HK2 expression is high in specific stages of early embryonic development [6] , [12] , [13] , [17] . HK2 is upregulated in tumours with greater transcriptional similarity with testicular germ cell cancer, a type of malignancy known for a strong stem-cell identity.…”

“…In addition, Np9 protein is reported to bind and regulate ubiquitin ligase MDM2, resulting in the repression of p53 tumour suppressor [11] . Transcripts of np9 and rec are found in human embryonic stem cells and human induced pluripotent stem cell lines and are associated with maintenance of pluripotency [12] , [13] , and recently it has been demonstrated that the activation and silencing of a specific HERV-K LTR LTR5HS is associated with reciprocal up-and downregulation of hundreds of human genes, and can occur over long genomic distances [14] .…”