LC3-associated phagocytosis at a glance

Abstract

Classically, canonical autophagy has been considered a survival mechanism initiated in response to nutrient insufficiency. We now understand that autophagy functions in multiple scenarios where it is necessary to maintain homeostasis. Recent evidence has established that a variety of non-canonical functions for autophagy proteins are mechanistically and functionally distinct from autophagy. LC3-associated phagocytosis (LAP) is one such novel function for autophagy proteins and is a contributor to immune regulation and inflammatory responses across various cell and tissue types. Characterized by the conjugation of LC3 family proteins to phagosome membranes, LAP uses a portion of the canonical autophagy machinery, following ligation of surface receptors that recognize a variety of cargos including pathogens, dying cells, soluble ligands and protein aggregates. However, instead of affecting canonical autophagy, manipulation of the LAP pathway in vivo alters immune activation and inflammatory responses. In this Cell Science at a Glance article and the accompanying poster, we detail the divergence of this distinctive mechanism from that of canonical autophagy by comparing and contrasting shared and unique components of each pathway.

Multiple phosphatidylinositol(3)phosphate roles in retinal pigment epithelium membrane recycling

“…TEM confirmed the accumulation of compartments containing POS disk membranes ( Fig 3C, S2). In control mice, the small number of Rho-containing phagosomes observed in RPE cells colocalized with LC3, indicating the presence of lipidated LC3 ( Fig 4A), as reported previously for POS phagocytosis (Kim et al, 2013;Frost et al, 2015) as well as for LC3-associated phagocytosis in other cell types (Heckmann and Green, 2019;Martinez et al, 2015). In contrast, in the KO RPE, LC3 did not colocalize with the accumulated Rho puncta, revealing defective LC3 recruitment and, presumably, defective lipidation on POS-containing phagosomes, in the absence of PI(3)P ( Fig 4A).…”

Lifting the innate immune barriers to antitumor immunity

“…This is a complex process that in some settings involves components of the autophagy machinery and is known as LC3-mediated phagocytosis or LAP. 177 Similar to the results from the activation of the efferocytosis receptors TAM and TIM-4 described above, engagement of LAP suppresses the inflammatory response. 178 179 Consistently, genetic ablation of LAP components in myeloid cells led to increase resistance to tumor growth in multiple models including B16F10 melanoma, LLC, MC38 adenocarcinoma and Kirsten rat sarcoma oncogen (KRAS)-driven lung cancer.…”

Dictyostelium discoideum and autophagy – a perfect pair

“…LC3-associated phagocytosis (LAP) is one such novel function for autophagy proteins and is a contributor to immune regulation and inflammatory responses across various cell and tissue types (Heckmann and Green, 2019). In contrast to canonical autophagy, LAP is not dependent on the AMPK-mTORC1-ULK1(ATG1) activation axis or nutrient status of the cells (Heckmann et al, 2017.…”

“…A plurality of ligands, including dying cells, immune complexes and pathogens, has been shown to facilitate the conjugation of LC3 to PE of the phagosome in this process. Several receptors that participate in cargo recognition have already been identified including toll-like receptors, immunoglobulin receptors or TIM4 (Heckmann and Green, 2019). Following an activating stimulus, LAP can be delineated into three phases, followed by lysosomal fusion.…”

“…2). The presence of LC3 on the phagosome, now termed LAPosome, mediates the fusion with the lysosome and the cargo is degraded (Heckmann and Green, 2019). LAP exists at the crossroads of phagocytosis and autophagy and is for example required for apoptotic corpse clearance during programmed cell death in multicellular organisms , Martinez et al, 2011.…”