Marchf8, also known as membrane-associated ring-CH-type finger 8, is an E3 ubiquitin ligase. It plays a crucial role in regulating the stability of various proteins, thus participating in multiple biological processes. It is involved in pathways such as autophagy, apoptosis, and immune-related signaling, and is of great biological importance in host-pathogen interactions and cell-fate determination. Genetic models, especially gene knockout (KO) mouse models, are valuable tools for studying its functions.

In HPV-positive head and neck cancer, MARCHF8 expression is upregulated by HPV oncoprotein E6-induced MYC/MAX transcriptional activation. Knockdown of MARCHF8 in human HPV-positive HNC cells restores cell-surface expression of TNFRSF death receptors and enhances apoptosis [1]. In mouse oral cancer cells expressing HPV16 E6 and E7, MARCHF8 knockout augments cancer cell apoptosis and suppresses tumor growth in vivo, suggesting its role in promoting tumor cell survival in this context [1]. Also, in HPV-positive HNC cells, MARCHF8 stabilizes the HPV oncoprotein E7 by degrading CUL1 and UBE2L3, components of the ubiquitin-ligase complex that would otherwise degrade E7. Knockdown of MARCHF8 decreases E7 protein levels while increasing CUL1 and UBE2L3 levels, and overexpression of CUL1 and UBE2L3 suppresses tumor growth in vivo [2,3].

In conclusion, MARCHF8 is a key E3 ubiquitin ligase involved in apoptosis regulation, virus-host interactions, and tumor-related processes. Findings from KO mouse models in HPV-associated head and neck cancer highlight its importance in understanding the disease mechanism, potentially providing new targets for cancer treatment strategies.

References:

1. Khalil, Mohamed I, Yang, Canchai, Vu, Lexi, Spanos, William C, Pyeon, Dohun. 2023. HPV upregulates MARCHF8 ubiquitin ligase and inhibits apoptosis by degrading the death receptors in head and neck cancer. In PLoS pathogens, 19, e1011171. doi:10.1371/journal.ppat.1011171. https://pubmed.ncbi.nlm.nih.gov/36867660/

2. Khalil, Mohamed I, Yang, Canchai, Vu, Lexi, Morgan, Iain M, Pyeon, Dohun. 2023. The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.11.03.565564. https://pubmed.ncbi.nlm.nih.gov/37961092/

3. Khalil, Mohamed I, Yang, Canchai, Vu, Lexi, Morgan, Iain M, Pyeon, Dohun. 2024. The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer. In Journal of virology, 98, e0172623. doi:10.1128/jvi.01726-23. https://pubmed.ncbi.nlm.nih.gov/38226814/