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

NLRP10 is an atypical member of the NLR family because it lacks a leucine-rich repeat domain at its C-terminus. Here, we show that in human epithelial cells and keratinocytes NLRP10 oligomerises in response to m-3M3FBS and SC-10 treatment. NLRP10 co-localises with ASC upon overexpression, but ASC nucleation and recruitment are different to NLRP3. While neither ATP hydrolysis nor the pyrin domain is required, the C-terminal tail region is both necessary and sufficient for oligomerisation. The generation of chimeric proteins shows that the tail region of human and mouse NLRP10 has a conserved function in oligomerisation but determines different protein stabilities. Changes in the subcellular localisation of NLRP10 and oligomerisation are dependent on the presence of evolutionarily conserved lysine residues in the tail region, which localise the majority of NLRP10 to 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 in NLRP10 activation with respect to other inflammasome-forming NLRPs and suggest a role of lipids in NLRP10 activation.

© 2026. The Author(s).

PMID: 42362760