NLRP6 self-assembles into a linear molecular platform following LPS binding and ATP stimulation

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• NOD-like receptors (NLRs) are crucial cytosolic sensors for innate immunity.
• The ligands and specificities of many NLRs, including NLRP6, are not fully understood.
• NLRP6 is vital for intestinal homeostasis and protection against diseases like colitis.

Purpose of the Study:

• To identify the ligand for NLRP6.
• To elucidate the molecular mechanism of NLRP6 activation.
• To reveal the structural basis of NLRP6-mediated inflammasome initiation.

Main Methods:

• Biochemical assays to detect direct binding of lipopolysaccharide (LPS) to NLRP6.
• Analysis of NLRP6 conformational changes and dimerization upon LPS stimulation.
• In vitro studies of NLRP6 assembly with ATP and ASC to form higher-order structures.

Main Results:

• Lipopolysaccharide (LPS), a major component of gram-negative bacteria, directly binds to NLRP6.
• LPS binding induces significant conformational changes and dimerization of NLRP6.
• ATP-stimulated NLRP6 dimers assemble into a linear platform, recruiting ASC to form higher molecular structures, suggesting a step-by-step activation process.

Conclusions:

• This study identifies LPS as a direct ligand for NLRP6.
• It reveals the structural architecture and assembly mechanism of a potential pre-inflammasome complex.
• The findings propose a novel molecular assembly pattern for immune receptor activation by bacterial components.