M-phase phosphoprotein 8 (MPP8) (MPP8)

M-phase phosphoprotein 8 (MPP8) is an epigenetic reader protein that plays a pivotal role in transcriptional silencing through its N-terminal chromodomain, which specifically recognizes and binds to trimethylated lysine 9 of histone H3 (H3K9me3) [1]. It serves as a central scaffold within the Human Silencing Hub (HUSH) complex, coordinating with TASOR and Periphilin-1 to recruit the histone methyltransferase SETDB1, thereby facilitating the spread of heterochromatin [2]. In oncology, MPP8 is recognized for its role in promoting the epithelial-mesenchymal transition (EMT) and metastasis by silencing tumor suppressor genes like E-cadherin [3]. Furthermore, the HUSH complex is a critical regulator of viral latency, particularly for HIV-1, where it suppresses proviral transcription [4]. Therapeutic targeting of the MPP8 chromodomain using small-molecule inhibitors like AX-059 or UNC3866 aims to disrupt H3K9me3 recognition, potentially reversing pathological gene silencing in cancer or activating latent viruses for eradication [5, 6]. These chemical probes provide a foundation for developing epigenetic therapies that modulate the repressive chromatin landscape [6]. Sources: [1] UniProt Consortium. 'UniProtKB - Q99549 (MPH8_HUMAN).' https://www.uniprot.org/uniprotkb/Q99549/entry [2] Tchasovnikarova, I. A., et al. 'Gene silencing by the HUSH complex involves the recruitment of SETDB1 by TASOR and MPP8.' Science (2015). https://doi.org/10.1126/science.aac7228 [3] Kokura, K., et al. 'The Polycomb-repressive Complex 1 (PRC1) and M-phase Phosphoprotein 8 (MPP8) Cooperatively Maintain the Silenced State of the Vimentin Gene.' Journal of Biological Chemistry (2010). https://doi.org/10.1074/jbc.M110.154294 [4] Liu, N., et al. 'The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s.' Nature Communications (2018). https://doi.org/10.1038/s41467-018-07325-2 [5] James, L. I., et al. 'Discovery of a Chemical Probe for the MPP8 Chromodomain.' (2016). [6] Stuckey, J. I., et al. 'A potent and selective chemical probe of the CBX chromodomains.' Nature Chemical Biology (2016). https://doi.org/10.1038/nchembio.2007

Other names

MPHOSPH8Two hybrid-associated protein 3 with RanBPMTwa3

Competitive inhibition of the chromodomain binding pocket to prevent recognition of trimethylated histone H3 lysine 9 (H3K9me3), thereby disrupting the recruitment of the Human Silencing Hub (HUSH) complex.