“Using the CRY to calm fire”: Establishing the role of circadian clock in NLRP3 regulation and functions. – ICARUS
Circadian clocks sustain rhythmic patterns in behavior and physiology and increase the flexibility of the organisms to adapt to cyclic changes in the environment. Disrupted circadian rhythmicity, a well-known aspect of modern-day society, promotes the pathophysiology of a wide variety of diseases. Compelling evidences suggest a major role for circadian clock in the NLRP3 inflammasome activation. Mutations of NLRP3 gene causes a rare set of inflammatory diseases called Cryopyrin-Associated Periodic Syndromes (CAPS). Interestingly, CAPS patients exhibit a circadian pattern of symptoms. Our original findings show that core clock components interact with NLRP3 and theses interactions are lost with NLRP3 CAPS mutants. Our main objective is to increase our understanding about the signaling pathways governed by circadian clock and study the consequences of circadian disruption on inflammatory diseases, especially on the development of CAPS. We propose to study a new perspective on the regulation between the circadian clock and immune response by looking at post-translational processes, especially protein interactions between clock proteins and NLRP3 inflammasome components. ICARUS will use recent biochemical approaches to address the complex nature of NLRP3 regulation by the circadian clock from a molecular scale to the whole animal and patients. This proposal resolves around three major hypotheses namely (i) the circadian clock acts as a molecular switch for NLRP3 functions, (ii) identification of a circadian deregulation of NLRP3 functions in CAPS diseases and (iii) NLRP3 is a modulator of the core clock. ICARUS proposes to fill important knowledge gap by elucidating the connection between the molecular clock and the innate immune response through the detailed characterization of the interaction between NLRP3 and circadian clock proteins and the reciprocal action of NLRP3 on the core clock regulation. A better understanding of the NLRP3 inflammasome assembly will also bring new insight on signaling pathways deregulated in CAPS disease with the aim to unravel novel therapeutic or prevention strategies that take circadian time into account.
Madame Anne-Laure HUBER (Centre de Recherche en Cancérologie de Lyon)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CRCL Centre de Recherche en Cancérologie de Lyon
Help of the ANR 279,720 euros
Beginning and duration of the scientific project: May 2021 - 36 Months