Dr Silvia Alvarez-Diaz has shown for the first time the important role played by proteins MLKL and RIPK3, and is using this information to help develop treatments for a range of diseases.
A form of regulated cell death known as necroptosis – and its role in health and disease – is the topic of new research by Walter and Eliza Hall Institute scientists.
An international team of scientists, led by the Institute’s Dr Silvia Alvarez-Diaz and Professor Andreas Strasser and Professor Doug Green from St Jude Children’s Hospital in the US, has shown for the first time the important and different role played by the proteins MLKL and RIPK3 as regulators of the necroptotic process in a pre-clinical model of autoimmune disease.
Dr Alvarez-Diaz said while apoptosis, the most well-known form of programmed cell death, has been well-established as an important process in the body’s ability to stave off cancers, autoimmune disorders and other diseases, less has been understood about necroptosis.
“Necroptosis, a form of regulated necrosis (harmful cell death), has gained increased interest in the scientific community because of its implication in several diseases, mainly severe inflammatory conditions, including pancreatitis or inflammatory bowel disease and possibly in cancer development,” Dr Alvarez-Diaz said.
RIPK3 and MLKL are proteins that play a vital role controlling the death of cells by necroptosis. These molecules both contribute to necroptotic cell death but RIPK3 can contribute not only to necroptosis but also to apoptosis and the production of cytokines, molecules that induce inflammation.
Dr Alvarez-Diaz said this was an important difference to take into account when developing new therapies that target necroptosis.
“Blocking RIPK3 or MLKL stops cells from dying by necroptosis and can be useful for the treatment of inflammatory diseases or even cancer. For this reason, a lot of research is currently being done to develop inhibitors of these molecules to be used in the clinic.
“We need to know how differently these two molecules behave in a similar context in order to know which one is the best target for a new drug, including what the possible side effects of targeting either of these proteins may be.”
The researchers have compared side-by-side the effect of blocking the activity of RIPK3 or MLKL in a pre-clinical model of autoimmune disease, autoimmune lymphoproliferative syndrome (ALPS) for the first time. ALPS is a rare genetic disorder that affects both children and adults.
“Defects that cause this disease also contribute to autoimmune diseases more generally. In ALPS some of the processes that control cell death do not work correctly and the body cannot properly regulate the number of lymphocytes, a type of white blood cells, and they accumulate in the lymph nodes, liver and spleen resulting in the pathological enlargement of these organs.
People with ALPS also develop autoimmune disorders and have an increased risk of developing cancers of white blood cells.
“We compared the effect of preventing necroptotic cell death by blocking RIPK3 or MLKL side by side in an ALPS predisposing context and found that while MLKL has no major effects, RIPK3 worsens the development and progression of this disease, mainly due to the non-necroptotic functions of RIPK3.
“By understanding how differently these molecules work and the different outcomes that we get by targeting each of these molecules we could develop new drugs that activate or deactivate the pathway and could be used for the treatment of a range of human diseases.”
The research has just been published in the journal Immunity. The work was funded by the National Health and Medical Research Council, the Australian Cancer Research Foundation, the U.S. NIH, the American Lebanese Syrian Associated Charities and the Victorian State Government Operational Infrastructure Support.
