Lipid biosynthesis and the NLRP3 inflammasome activation
Author(s)
Leishman, Stuart
Type
Thesis
Abstract
Our understanding of the immune system has advanced considerably in recent years; however, each new discovery brings further questions. One major finding in innate immunity is the NLRP3 inflammasome, a multiprotein complex that initiates programmed cell death through both canonical (caspase-1 mediated) and non-canonical (caspase-11 mediated) pathways. Lipids play essential roles in cellular processes, including development and metabolism. Fatty acid synthase (FASN), a homodimeric enzyme, is critical for cell growth and metabolic homeostasis by converting malonyl-CoA and acetyl-CoA into palmitate, a saturated fatty acid that serves as a precursor for longer-chain lipids. Additionally, palmitate can modify proteins through palmitoylation, binding to cysteine residues in target proteins to ensure their proper localization and function. My research demonstrates that inhibiting FASN with small-molecule inhibitors significantly suppresses NLRP3 activity, preventing the cleavage of downstream caspase-1 and Gasdermin D, and blocking the maturation of the pro-inflammatory cytokine IL-1β. Furthermore, I discovered that FASN activity is required for the palmitoylation of NLRP3 at the Cys898 site, a modification critical for NLRP3 localization to the dispersed trans-Golgi network, the site of inflammasome assembly. Additionally, large-scale untargeted mass spectrometry was conducted to map the cellular landscape of inflammasome activation. This unprecedented snapshot revealed various lipid classes influenced by both the canonical and non-canonical pathways. These findings provide new insights into the lipid-dependent regulation of NLRP3 and uncover novel mechanisms of inflammasome activation.
Date Issued
2025-01-24
Date Awarded
01/05/2025
Advisor
Anand, Paras
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)