MLKL’s Role in Necroptosis Revealed

New research from the Walter and Eliza Hall Institute sheds light on the inflammatory cell death regulatory protein MLKL and its role in disease. In a trio of studies published today in Nature Communications, the team used advanced imaging to visualize key steps in the activation of MLKL, revealing previously unseen details about how this protein drives necroptosis. They also showed that inherited variants of MLKL are connected to a human inflammatory disease.

"While MLKL and necroptosis protect our bodies from infections, excessive necroptosis has been linked with inflammatory conditions such as inflammatory bowel diseases," senior author James Murphy explained. "Our research team has taken several complementary approaches to better understand how MLKL functions, which could improve the understanding and treatment of diseases involving excessive necroptosis."

One of the studies used advanced imaging technologies to watch the MLKL protein in cells as they underwent necroptosis. According to Andre Samson, one of the study leaders, this identified two important 'checkpoints' in necroptosis. "We could see how MLKL changed its location as necroptosis occurred, clumping and migrating to different parts of the cell as the cell progressed towards death," he said.

"Intriguingly, we could see activated MLKL gather at the junctions between neighbouring cells—potentially suggesting a way for one dying cell to trigger necroptosis in surrounding cells, which could be a form of protection against infections."

Another study, led by Joanne Hildebrand and Maria Kauppi, examined links between alterations in the MLKL protein and inflammatory conditions. Dr Hildebrand said the team isolated a variant of MLKL that caused a lethal inflammatory condition in laboratory models. "We discovered this form of MLKL contained a single mutation in a particular region of the protein that made MLKL hyperactive, triggering necroptosis and inflammation," she explained.

"By searching genome databases, we discovered similar variants in the human MLKL gene are surprisingly common—around ten per cent of human genomes from around the world carry altered forms of the MLKL gene that result in a more-easily activated, more inflammatory version of the protein.

The team speculated that the pro-inflammatory variant of MLKL might be associated with inflammatory diseases. "We looked more closely at databases of genomes of people with inflammatory diseases to understand the prevalence of MLKL variants. Indeed, people with an autoinflammatory condition chronic recurrent multifocal osteomyelitis (CRMO) were much more likely to carry two copies of a pro-inflammatory variant of the MLKL gene than people without an inflammatory disease.”