Alternative splicing regulates stochastic NLRP3 activity

Area of Science:

• Molecular Biology
• Immunology
• Genetics

Background:

• Leucine-rich repeat (LRR) domains are crucial, conserved protein structures involved in development and immunity.
• Alternative splicing (AS) is a key mechanism for generating protein diversity from a limited number of genes.

Purpose of the Study:

• To investigate the role of exonic modularity in LRR domains concerning alternative splicing.
• To examine the impact of AS on Nod-like receptors, particularly the NLRP3 inflammasome sensor.

Main Methods:

• Analysis of exonic structure in human LRR-containing gene families.
• Identification and characterization of alternative splicing variants of NLRP3 in human and mouse.
• Functional assessment of NLRP3 isoforms, including interaction studies with NEK7.

Main Results:

• Strict exonic modularity was observed in LRR domains, enabling alternative splicing.
• Human NLRP3 exhibits AS, producing a major isoform lacking exon 5 (NLRP3 Δ exon 5).
• NLRP3 Δ exon 5 lacks the NEK7 interaction site, leading to a loss of inflammasome activity.

Conclusions:

• Alternative splicing of LRR domains represents a novel regulatory mechanism in vertebrate innate immunity.
• Differential utilization of LRR modules via AS, as seen in human NLRP3, critically affects immune signaling pathways.