Elucidation of a new regulatory mechanism involving ubiquitination of cell death suppressor proteins
A research group led by Professor Hiroyasu Nakano at the Department of Biochemistry, Toho University Faculty of Medicine, identified Mind bomb (MIB)2 as an enzyme that ubiquitinates and modifies the protein cFLIP, which plays a central role in suppressing cell death. This finding indicates that ubiquitination of cFLIP by MIB2 plays an essential role in suppressing caspase 8-mediated cell death, suggesting that ubiquitination of cFLIP may be a promising target for development of therapies to control cell death.These results were published in the American scientific journal “Communications Biology” on January 19, 2021.
Summary Professor Nakano’s research group has demonstrated that Mind bomb (MIB)2, a ubiquitin ligase, binds to and directly ubiquitinates the cell death suppressor protein cFLIP. In MIB2-deficient cells, cFLIP ubiquitination was attenuated, but its degradation was rather decreased, indicating that MIB2-mediated ubiquitination does not promote cFLIP degradation. Intriguingly, TNF-induced apoptosis was enhanced in MIB2-deficient cells.
Prof. Hiroyasu Nakano
Taken together, these results show that MIB2-mediated ubiquitination is necessary for cFLIP to inhibit cell death. cFLIP has previously been shown to associate with caspase 8 and inhibit apoptosis. Ubiquitination of cFLIP by MIB2 may alter the higher-order structure of the complex containing caspase 8, preventing it from forming a large complex, thereby preventing caspase 8 association (Fig. 1). This study has revealed for the first time that MIB2 is a ubiquitin ligase that acts on cFLIP, and cFLIP ubiquitination by MIB2 is essential to activate its cell death inhibitory function. This research encourages future development of cell death-promoting drugs targeting the interaction between MIB2 and cFLIP.
Fig. 1. MIB2 blocks caspase 8 activation through ubiquitylation of cFLIP. MIB2 constitutively binds and ubiquitylates cFLIP. Upon TNF stimulation, caspase 8 and ubiquitylated cFLIP are recruited to the death-inducing complex. Ubiquitylated cFLIP prevents a proper oligomer formation with caspase 8, thereby suppressing caspase 8 activation and apoptosis.
Key points of the research
Mind bomb (MIB)2 is an enzyme that ubiquitinates and modifies the protein cFLIP, which plays a central role in suppressing cell death.
Ubiquitination of cFLIP by MIB2 is required to enhance cFLIP’s cell death inhibitory activity.
Abnormalities in cell death regulatory mechanisms have been observed in various diseases, including cancer and neurodegenerative diseases. This study suggests that if we can pharmacologically inhibit cFLIP ubiquitination, we may be able to induce cell death more efficiently in cancer cells.
This research was conducted in collaboration with researchers of different institutions, including Prof. Tatsuya Sawasaki of Ehime University, Dr. Yasushi Saeki of Tokyo Metropolitan Institute of Medical Science, Dr. Fumiaki Ohtake of Hoshi University, and Prof. Fuminori Tokunaga of Osaka City University.
