Mutation in IL 36 RN impairs the processing and regulatory function of the interleukin‐36‐receptor antagonist and is associated with DITRA syndrome

The identification of loss‐of‐function mutations of the IL 36 RN gene encoding the interleukin‐36 receptor antagonist ( IL ‐36Ra) in generalized pustular psoriasis ( GPP ) emphasized the key role of this pathway in skin innate immunity and systemic inflammation. It has been previously shown in vitro that removal of the N‐terminal amino acid IL 36Ra (M1) is critical to its biological activity, but the in vivo contribution of this processing remains unknown. We report herein a new homozygous (c4G>T, pV 2F) missense IL 36 RN mutation segregating in a family with three GPP ‐affected patients. The V2F mutation does not alter IL ‐36Ra protein expression but was devoid of any antagonist activity. Mass spectrometry showed that the V2F IL ‐36Ra mutant retains its first N‐terminal methionine. These results provide the first in vivo demonstration that removal of N‐terminal methionine of native IL ‐36Ra is a mandatory step to reach optimal antagonist activity and to prevent sustained skin and systemic inflammation in humans.