Toho university scientists find new mechanism to keep cell death pathway suppressed

January 27, 2021

In our body, unnecessary cells are removed by regulated cell death. Understanding of the mechanism underlying regulated cell death is critical for the development of therapies for many diseases. Professor Nakano's research group has demonstrated that Mind bomb-2 (MIB2), a ubiquitin ligase, binds to and directly ubiquitinates the cell death suppressor protein cFLIP (Cellular FLICE-inhibitory protein). cFLIP is encoded by CFLAR gene; alternative splicing results in two forms, the long form (cFLIPL) and the short form (cFLIPs). cFLIPL plays a dominant role in suppression of cell death. In MIB2-deficient cells, cFLIPL ubiquitination was attenuated, but its degradation was rather decreased, indicating that MIB2-mediated ubiquitination does not promote cFLIPL degradation. Intriguingly, TNF-induced apoptosis was enhanced in MIB2-deficient cells. Taken together, these results show that MIB2-mediated ubiquitination is necessary for cFLIPL to inhibit cell death. cFLIPL has previously been shown to associate with caspase 8 and inhibit apoptosis. Ubiquitination of cFLIPL 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).

"The protein cFLIPL has been known to play a central role in the regulation of cell death. We screened hundreds of ubiquitin ligases for the ones that interact with cFLIP protein, and found MIB2. MIB2 has been known to be involved in the Notch signaling pathway," Dr. nakabayashi, lead author of the study said. "Here we found a new role for this ubiquitin ligase. Our study has revealed for the first time that MIB2 is a ubiquitin ligase that acts on cFLIPL, and cFLIPL ubiquitination by MIB2 is essential for the cFLIP's function in suppressing cell death signaling. This research encourages future development of cell death-promoting drugs targeting the interaction between MIB2 and cFLIPL."

"Abnormalities in cell death regulation have been observed in various diseases, including cancers and neurodegenerative diseases. Our study suggests that if we can pharmacologically inhibit cFLIP ubiquitination, we may be able to induce cell death more efficiently in cancer cells," said Prof. Nakano, senior author of the study.
-end-
These results were published in Communications Biology, on January 19, 2021. This research was conducted in collaboration with 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.

Toho University

Related Cell Death Articles from Brightsurf:

Cell death in porpoises caused by environmental pollutants
Environmental pollutants threaten the health of marine mammals. This study established a novel cell-based assay using the fibroblasts of a finless porpoise stranded along the coast of the Seto Inland Sea, Japan, to better understand the cytotoxicity and the impacts of environmental pollutants on the porpoise population.

Gold nanoparticles to save neurons from cell death
An international research team coordinated by Istituto Italiano di Tecnologia in Lecce (Italy) has developed gold nanoparticles able to reduce the cell death of neurons exposed to overexcitement.

New light shone on inflammatory cell death regulator
Australian researchers have made significant advances in understanding the inflammatory cell death regulatory protein MLKL and its role in disease.

Silicones may lead to cell death
Silicone molecules from breast implants can initiate processes in human cells that lead to cell death.

New players in the programmed cell death mechanism
Skoltech researchers have identified a set of proteins that are important in the process of apoptosis, or programmed cell death.

Tumors hijack the cell death pathway to live
Cancer cells avoid an immune system attack after radiation by commandeering a cell signaling pathway that helps dying cells avoid triggering an immune response, a new study led by UTSW scientists suggests.

How trans fats assist cell death
Tohoku University researchers in Japan have uncovered a molecular link between some trans fats and a variety of disorders, including cardiovascular and neurodegenerative diseases.

Bacteria can 'outsmart' programmed cell death
To be able to multiply, bacteria that cause diarrhoea block mediators of programmed cell death, a new study in 'Nature Microbiology' shows.

Cell death or cancer growth: A question of cohesion
Activation of CD95, a receptor found on all cancer cells, triggers programmed cell death -- or does the opposite, namely stimulates cancer cell growth.

Cell death blocker prevents healthy cells from dying
Researchers have discovered a proof-of-concept drug that can prevent healthy cells from dying in the laboratory.

Read More: Cell Death News and Cell Death Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.