Structural and functional consequences of IL33 and IL1RL1 coding variants on IL-33/ST2 signaling

Area of Science:

• Immunology
• Genetics
• Hematology

Background:

• Interleukin-33 (IL-33) is a key regulator of immunity and inflammation.
• Genetic variations in IL33 and its receptor IL1RL1 (ST2) are linked to diseases like asthma.
• Emerging evidence suggests IL-33 also plays a role in hematopoiesis and platelet biology.

Purpose of the Study:

• Investigate the functional impact of two missense variants (IL33 p.Tyr129His and IL1RL1 p.Gln501Arg) found in a patient with thrombocytopenia.
• Determine the structural and functional consequences of these variants on IL-33/ST2 signaling.
• Explore the potential role of the IL-33/ST2 pathway in platelet homeostasis.

Main Methods:

• Utilized structural modeling to analyze the impact of IL-33 Y129H and IL1RL1 Q501R variants on protein complex formation.
• Performed functional assays to assess binding affinity and biological activity of the variants.
• Examined the effect of IL1RL1 Q501R on the Toll/IL-1 receptor (TIR) domain and adapter protein recruitment.

Main Results:

• The novel IL33 variant p.Tyr129His was identified as a loss-of-function variant, significantly reducing binding affinity and biological activity.
• Structural modeling showed IL-33 Y129H disrupts a critical hydrogen bond in the IL-33/ST2 complex.
• The IL1RL1 p.Gln501Arg variant perturbs the TIR domain, potentially affecting MyD88 recruitment and downstream signaling, offering a mechanism for its protective association with asthma.

Conclusions:

• These findings provide crucial structural and functional insights into clinically relevant IL33 and IL1RL1 variants.
• The simultaneous presence of these variants in a thrombocytopenic patient highlights a potential role for the IL-33/ST2 pathway in platelet homeostasis and stress hematopoiesis.