Better Together: Current Insights Into Phagosome-Lysosome Fusion.

Jenny A Nguyen,Robin M Yates

doi:10.3389/fimmu.2021.636078

Abstract

Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently kill and digest engulfed microbes, cells, and debris. The fusion of phagosomes with lysosomes is a principal driver of phagosomal maturation and is targeted by several adapted intracellular pathogens. Impairment of this process has significant consequences for microbial infection, tissue inflammation, the onset of adaptive immunity, and disease. Given the importance of phagosome-lysosome fusion to phagocyte function and the many virulence factors that target it, it is unsurprising that multiple molecular pathways have evolved to mediate this essential process. While the full range of these pathways has yet to be fully characterized, several pathways involving proteins such as members of the Rab GTPases, tethering factors and SNAREs have been identified. Here, we summarize the current state of knowledge to clarify the ambiguities in the field and construct a more comprehensive phagolysosome formation model. Lastly, we discuss how other cellular pathways help support phagolysosome biogenesis and, consequently, phagocyte function.

Highlights

Professional phagocytes, such as macrophages, dendritic cells (DCs), and neutrophils, are critical to the innate immune response and the maintenance of homeostasis through their ability to ingest and degrade microbes, debris, and dying cells [1]
The Rab GTPases Rab7, Rab2 and Rab14 participate in tethering phagosomes and lysosomes albeit through mechanisms that are less known for Rab2 and Rab14
Rab7 recruits tethering effectors, whereby the individual subunits of the homotypic fusion and vacuole sorting (HOPS) complex give it the multifunctional capacity to serve as a Rab guanine exchange factor (GEF), a tether and an Sec1/ Munc18 (SM) protein that catalyzes soluble NSF attachment protein receptor (SNARE) assembly

Summary

Introduction

Professional phagocytes, such as macrophages, dendritic cells (DCs), and neutrophils, are critical to the innate immune response and the maintenance of homeostasis through their ability to ingest and degrade microbes, debris, and dying cells [1]. The fusion of the phagosome with lysosomes forms the mature phagolysosome (PL) which has full degradative and microbicidal capacity. Heterotypic fusion between the phagosome and lysosome is imperative for phagocytes to carry out their functions in immunity and homeostasis and is a tightly regulated process. The importance of membrane fusion in Current Insights Into Phagosome-Lysosome Fusion phagocyte function is further highlighted by the myriad of mechanisms various pathogens have developed which impede fusion machinery in order to prevent PL formation, and the microbicidal environment that is established. Gramnegative bacteria Mycobacterium tuberculosis and Coxiella burnetii, parasites of the Leishmania genus and the fungi Aspergillus fumigatus can inhibit PL fusion to avoid death in phagosomes, among many others [5,6,7,8,9]

Objectives

Conclusion