There is compelling evidence that excessive production of interleukin-1b
(IL1b) plays a dominant role in the pathophysiology of autoinflammatory
diseases (AID), as most impressingly shown by the success of targeted
IL1β-antagonizing therapies. Elevated IL1β production is regulated by two
major events including an increased transcription of the IL1β gene as well as
an enhanced caspase-1-mediated proteolytic maturation of the inactive IL1b
precursor. Caspase-1 activity is controlled at inflammasomes, which are
multimolecular complexes composed of NLRP proteins, different adapters
and proinflammatory caspases.
How the activities of inflammasomes are regulated at the molecular level is
poorly understood. In the last funding period we have focused on
posttranslational modifications of the NLRP3 inflammasome and found a
hitherto unknown stimulation-dependent serine phosphorylation of NLRP3,
promoting inflammasome assembly and IL1b processing. We will now
identify the responsible NLRP3 kinase and study its regulation in AID. In
addition, we discovered that a novel atypical member of the inhibitor of
NFkB family, IkB-Zeta, is a strong activator of IL1β transcription. Whereas IκB-Zeta
can transcriptionally induce a defined subset of target genes, its activity
appears to be antagonized by IkB-NS, a related IkB protein. We will therefore
further investigate the regulation of both atypical IκB proteins and their role
for IL1b production in AID patients.