C-terminal lysine residues localise NLRP10 at lipid compartments and govern NLRP10 oligomer formation

NLRP10 is an atypical member of the NOD-like receptor (NLR) family because it lacks a leucine-rich repeat domain at its C-terminus. Recently, NLRP10 has been shown to form an inflammasome, however, the mechanism and the trigger of activation remain elusive. Here, we show that in human epithelial cells and keratinocytes NLRP10 oligomerises in response to the stressor m-3M3FBS. NLRP10 co-localises with ASC upon overexpression, but ASC nucleation and recruitment were different to other NLRPs. While neither ATP hydrolysis nor the pyrin domain were required, the C-terminal tail region (aa 584-655) was both necessary and sufficient for oligomerisation. Generation of chimeric proteins showed that the function of the tail is conserved between human and mouse NLRP10 in respect to aggregation but convers different protein stability. Changes in the subcellular localisation of NLRP10 and oligomerization were dependent on the presence of evolutionarily conserved lysine residues in the tail region, which localise the majority of NLRP10 at lipid droplets. Our study identifies the C-terminal basic tail of NLRP10 as a key regulatory element for oligomerisation and localisation at lipid interfaces. These findings underline differences of NLRP10 activation in respect to other inflammasome forming NLRPs and suggest a role of lipids in NLRP10 activation.