Understanding how lipids activate LC3-associated phagocytosis

LC3-associated phagocytosis (LAP) is a specialized process for degrading dead cells, microbes or other particles. It plays a role in innate immunity, inflammation regulation and anticancer responses. St. Jude Children's Research Hospital scientists have, for the first time, implicated lipids in the cellular mechanism that initiates LAP. The findings, published today in Nature Cell Biology, shed light on how this process begins and its potential to influence tumor immunity. 

During LAP, specialized cells engulf unwanted material into membrane-bound compartments called phagosomes. The protein LC3 is then recruited to help break down the compartment's contents. Previous research led by corresponding author Doug Green, PhD, St. Jude Department of Immunology, demonstrated that blocking LAP promotes an enhanced anticancer response in the tumor microenvironment, highlighting its role in regulating immunity. 

Despite these findings, the molecular mechanism driving LAP initiation was unknown. LAP can be triggered by diverse stimuli, such as dead cells, antibody-bound particles or pathogens, raising the fundamental question of how the cell recognizes these different signals and activates the same molecular process. 

Understanding the signals that initiate LAP offers opportunities to leverage LAP for therapeutic purposes and target it in the tumor microenvironment to promote anticancer immunity."

Doug Green, PhD, St. Jude Department of Immunology

Green's team found the answer lies with a lipid. 

The lipid connection: A lipid lets cells LAP it up 

The researchers report that a novel mechanism activates LAP. Ligands that engage LAP induce enrichment of the lipid phosphatidylserine in the phagosome membrane. This enrichment subsequently recruits the Rubicon-containing PI3-kinase complex required to start the enzymatic cascade that triggers LAP. Thus, these interactions comprise the signal transduction pathway required to initiate LAP. 

This study provides the first evidence that specific lipids play a regulatory role in LAP. The findings align with the fact that phagocytosis is a membrane-driven process, with lipids playing a central role in membrane dynamics. 

"While phosphatidylserine is typically found on the inner leaflet of membranes, its functional role there wasn't well understood," said first author Emilio Boada-Romero, PhD, Department of Immunology. "It turns out this lipid acts as a docking site for proteins, which adds an exciting layer to our understanding of its function." 

The discovery of this phosphatidylserine-driven mechanism not only clarifies how LAP is initiated but also highlights the importance of lipid signaling in immune regulation. These findings open new avenues for exploring therapeutic strategies to modulate LAP in diseases such as cancer and autoimmune disorders, where its role in immunity and inflammation could be harnessed for treatment. 

Authors and funding 

The study's other authors are Clifford Guy, Gustavo Palacios, Luigi Mari, Suresh Poudel, Zhenrui Li and Piyush Sharma of St. Jude. 

The study was supported by grants from the U.S. National Institutes of Health (R35CA231620), the European Molecular Biology Organization Postdoctoral Fellowship (ALTF 1526-2016) and ALSAC, the fundraising and awareness organization of St. Jude.