Study finding helps better comprehend necroptosis for treating diseases

A group of scientists from WEHI, for the first time, visualized a human cell death complex associated with autoimmune and inflammatory conditions like inflammatory bowel disease, and injuries connected to exorbitant cell death.

Dr Katherine Davies and Yanxiang Meng have visualized a human cell death complex linked to autoimmune and inflammatory conditions for the first time. Image Credit: Walter and Eliza Hall Institute of Medical Research.

The researchers utilized the Australian Synchrotron to solve the structure of the human cell death proteins RIPK3 and MLKL linked to each other, and also human RIPK3 alone. Upon activation of MLKL by RIPK3, a kind of inflammatory cell death known as necroptosis—destroying the cells and alerting the immune system that it encounters attack—is triggered. But uncontrolled necroptosis is associated with human inflammatory diseases.

The observations would help researchers identify drugs that can pinpoint and suppress cell death by necroptosis. This could help in the generation of novel treatments for a range of inflammatory and autoimmune diseases in addition to renal injury, inflammatory bowel disease, and diabetes.

The research was headed by WEHI scientists Yanxiang Meng, Dr Katherine Davies, Associate Professor Peter Czabotar, and Associate Professor James Murphy. The observations are the latest in a nearly 15-year-long journey to comprehend necroptosis for treating diseases. The study was published in the Nature Communications journal.

At a glance

• Scientists from WEHI visualized the structures of human cell death protein RIPK3 alone, and RIPK3 bound to MLKL in a dormant state.
• This is the first time researchers visualized these cell death proteins in humans alone and in complex providing them with a deeper visual understanding of what induces the dormant complex to activate and destroy cells.
• The study could lead to the development of novel therapies for conditions linked with excessive inflammatory cell death, like ischemia-reperfusion injury in kidney and heart tissues, inflammatory bowel disease, and diabetes.

“The cell death pathway”

Necroptosis is a kind of inflammatory cell death mechanism that aids in protecting the body against infection. They are mostly induced when a cell is infected by bacteria or a virus. The cell is instructed to die and pass inflammatory signals to alert the immune system of foreign invaders. Necroptosis, however when excessive or uncontrolled, the inflammatory response can induce disease.

According to PhD student Yanxiang Meng, MLKL and RIPK3 are found in an inert state in all cells of the body, waiting to be activated.

MLKL and RIPK3 form an inert complex, with RIPK3 ‘holding’ MLKL in an inactive state to prevent necroptotic cell death. When the cell is infected, RIPK3 chemically modifies MLKL then detaches, giving it a ‘license to kill’ the infected or damaged cell for the greater good.”

Yanxiang Meng, PhD Student, Walter and Eliza Hall Institute of Medical Research

He stated that the Australian Synchrotron and Collaborative Crystallisation Centre (C3) facility at CSIRO were vital in visualizing the structure of human forms of RIPK3 bound to human MLKL for the first time.

The necroptotic cell death proteins are conserved across different organisms, however, there are differences between the proteins’ structures in different animals and how they bind to each other. We showed that the human versions of these proteins bind differently to what we have seen in other species. This is something the scientific community has been waiting many years for.”

Yanxiang Meng, PhD Student, Walter and Eliza Hall Institute of Medical Research

New targets for drug discovery

Dr Davies remarked that the researchers expect that this structural information could, in the future, direct novel treatment options for patients suffering from diseases associated with excessive necroptosis.

We now have a picture of how two key proteins in this death pathway are maintained in their dormant state. It would be interesting to know how this is regulated and leads to disease and whether this could be targeted with small-molecule drugs.”

Dr Katherine Davies, Walter and Eliza Hall Institute of Medical Research

Cells undergoing necroptosis. Video Credit: Walter and Eliza Hall Institute of Medical Research.