Nat Commun: Revealing new features of inflammatory cell death regulators!

, June 22, 2020 /

BIOON/-- Researchers at the Walter and Eliza Hall Institute of Medicine in Australia have made significant progress in understanding the inflammatory cell death-regulating protein MLKL and its role in diseaseIn three studies published today in the journal Communications Nature, the team used advanced imaging techniques to visualize key steps in MLKL activation, revealing previously unseen details about how the protein drives a form of death in an inflammatory cell called necrosisThey also showed for the first time that the geneticvariants of MLKLare associated with inflammatory diseases in humansBy detecting sequence changes in human MLKL and comparing the structure of MLKL proteins in different animals, the team also provided evidence that MLKL had been subjected to evolutionary stress, possibly because of its role in preventing infectionthis multidisciplinary study led by DrAndre Samson, DrJoanne Hildebrand, DrMaria Kauppi, MsKatherine Davies, Associate Professor Edwin Hawkins, Associate Professor Peter Czabotar, Professor Warren Alexander, Professor John Silke and Associate Professor James Murphyphoto source: Walter and Eliza Hall Institute (adapted from video videoed in Samson et al, Communications)understand that inflammatory cell deathcell death is a way for the body to protect itself from disease by removing unwanted or dangerous cellsIn some cases, such as viruses orbacteria infection, dead cells can cause inflammation to protect neighboring cells from infection This form of cell death is called necrotised apoptosis and is strictly controlled by specific proteins within the cell Associate Professor James Murphy says MLKL protein is an important regulator of necrosis "While MLKL and necrosis can protect our bodies from infection, excessive necrosis is associated with inflammation, such as inflammatory bowel disease," he said Our research team has taken several complementary approaches to better understand the function of MLKL, which can improve understanding and treatment of diseases involved in excessive necrosis A study led by Dr Andre Samson used advanced imaging techniques to observe MLKL proteins in necrotic cells Dr Samson said the study identified two important "checkpoints" for necrosis "We can see how MLKL changes its position when necrosis occurs, gathers and migrates to different parts of the cell as it approaches death," he said Interestingly, we can see that activated MLKLs gather at the connections of adjacent cells -- which may suggest a way for a dead cell to trigger a necrosis of surrounding cells, which may be a form of preventing infection "
the role of MLKL in inflammatory diseases
Dr Joanne Hildebrand and Dr Maria Kauppi studied the link between changes in MLKL proteins and inflammatory conditions Dr Hildebrand said the institute's researchers isolated a MLKL variant that causes fatal inflammation in a laboratory model "We found that this form of MLKL contains a single mutation in a specific area of the protein that makes MLKL hyperactive, causing necrosis and inflammation," she said By searching the genome database, we found that similar mutations in the human MLKL gene are surprisingly common -- about 10 percent of the human genome worldwide carries a mutated form of MLKL gene, resulting in proteins that are more likely to activate and trigger inflammation "
team speculated that the pro-inflammatory variant of MLKL may be related to inflammatory diseases " We looked more closely at the genome database of patients with inflammatory diseases to understand the prevalence of MLKL mutations In fact, people with chronic recurrent polylesionstochyremyelitis (CRMO) are more likely to carry two pro-inflammatory variants of the MLKL gene than people without inflammatory diseases This is the first time that mutations in MLKL have been linked to inflammatory diseases in humans Dr Hildebrand said the evolutionary pressure MLKL Dr Hildebrand said the high frequency of MLKL mutations in humans around the world suggested that more inflammatory protein variants may have benefited from evolution at some stage in human history "The possibility of stronger inflammatory forms of MLKL means that some people are better able to fight infectious diseases than those who only have the less easily activated MLKL protein," she said In another paper , Ms Katherine Davies led a study that used the Australian Synchrotron and CSIRO Synergy Crystallization Center to study the three-dimensional structure of MLKL in different vertebrates Photo Source: Nature Communications
Often, when a protein is found in different vertebrate species, the proteins of different species have similar structures and are preserved during evolution, Dr Davies said "To our surprise, there are significant differences in the structure of MLKL between vertebrates, even among species that are close to kinship, such as rats and mice In fact, MLKL in rats is so different from mlKL in mice that rat proteins don't work in mouse cells -- which is surprising because many proteins are interchangeable between the two species We believe that as vertebrates evolve, evolutionary pressures such as infection may have led to significant changes in MLKL Animals with the variant form MLKL may survive under certain pressures more than other animals, causing MLKL to accumulate changes much faster than many other proteins The "
" combined with data from human MLKL mutations suggest that MLKL is essential for cell balance for good inflammation, which protects cells from infection, and harmful inflammation that can lead to inflammatory diseases "
long-term research has paid off
said James Murphy, an associate professor at the university' research, which began 13 years ago with an inflammatory mutation in MLKL, when its role in necrosis was unclear Associate Professor James Murphy, of , said: "Our latest findings, completed by a multidisciplinary research team, have contributed to a huge advance in the field of necrosis, adding a lot of detail to the field of MLKL This will greatly facilitate the study of a range of inflammatory diseases Our team and others are already developing new drugs to reduce MLKL-driven inflammation, which we hope will be a new way to treat a range of inflammatory diseases (BioValleyBioon.com) References: New Light shone on cell cell cell s
hone Hildebrand, J.M., Kauppi, M., Majewski, I.J et al.
A missense dati at the MLKL brace region promotes spental de al-disaindauitic Nat Commun 11, 3150 (2020) https://doi.org/10.1038/s41467-020-16819-z
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