Under the right conditions, TNFR1 and other TNF superfamily "death receptors" can trigger a form of programmed cell death called ‘necroptosis’. Necroptosis has been implicated in the aetiology of several inflammatory diseases and therefore understanding how and when it occurs has important therapeutic implications. The pseudokinase Mixed Lineage Kinase domain-Like (MLKL), functions down stream of RIPK1 and RIPK3 activation and is absolutely required for necroptosis. Indeed it appears to be the final executioner although the mechanism by which it kills cells remains unclear.

We have identified a mouse strain with a single base pair missense in the gene encoding MLKL. This mutation converts the MLKL  protein into an auto[activated form that does not require RIPK3 to activate it in order to kill cells. However, mice homozygous for this mutant allele, Mlkl^plt15, are born at expected Mendelian ratios and are indistinguishable from wild type littermates at birth. They do however, distinct to the hetoerozygotes, rapidly deteriorate and die 2-6 days after birth with elevated circulating pro-inflammatory cytokines and multi-organ damage.

I will discuss how analysis of this mutant has led to important insights into how MLKL is regulated both at the molecular and cellular level.