Inositol Hexakisphosphate Plays Crucial Role in Necroptosis

Inositol Hexakisphosphate Plays Crucial Role in Necroptosis

When cells die they can do so quietly or they can release signals to other cells alerting them to a threat to allow them to prepare. The latter type of cell death is known as necroptosis. While the mechanism by which necroptosis occurs was largely known, new research has revealed an important part of the final stage of the process.

Researchers at Stanford University School of Medicine have identified a compound that unlocks the ability of a protein to cause necroptosis. Without that key, necroptosis does not occur. Necroptosis requires a protein called MLKL, called the “‘executioner” protein, by Jan Carette, PhD, assistant professor of microbiology and immunology at Stanford’s School of Medicine and senior author of the new study.

The MLKL protein allows the cell contents to escape by making holes in the cell membrane. While the MLKL protein had previously been identified as critical to the final stages of necroptosis, what was not known is the protein needed to be activated before it can perform its killer function.

The Stanford University team of researchers identified the molecule that turns the benign protein into its killer alter ego. That final stage requires an inositol phosphate, or more specifically, inositol hexakisphosphate or IP6.

IP6 can be considered a kill code that activates the executioner protein. Without that kill code, the protein is harmless. Only when IP6 binds to the protein does it serve as executioner.

All of the constituent parts of the protein are present in the cell, and in order for it to be assembled, other proteins and signalling molecules are required. Even if those processes take place, without IP6, MLKL will not trigger necroptosis. Other inositol phosphates such as IP3 do not activate MLKL.

When cells die via necroptosis, signal are released to other cells which allow defenses to be implemented or preparations to be made for necroptosis. While necroptosis is an important function in the response to viruses or other invaders, the process can also be triggered by autoimmune diseases such as multiple sclerosis and inflammatory bowel disease.

Now that this vital piece of the puzzle has been identified, it may be possible to develop new treatments to block necroptosis, such as blocking the IP6 binding site on MLKL or convincing the protein to bind to IP3, to prevent IP6 from binding.

The study – MLKL Requires the Inositol Phosphate Code to Execute Necroptosis – has recently been published in the journal Molecular Cell.

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