Better Together: Current Insights Into Phagosome-Lysosome Fusion

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.

LAPped in Proof: LC3‐Associated Phagocytosis and the Arms Race Against Bacterial Pathogens

“…Such effectors may be critical for LAP evasion. However, as phagosome–lysosome fusion is a highly dynamic process that depends on membrane lipid composition and the coordinated action of Rab GTPases, tethering factors and SNAREs ( Nguyen and Yates, 2021 ), details of the evasion strategies counteracting lysosomal fusion have yet to be substantiated.…”

“…Following LC3-decoration, the LAPosome will rapidly fuse with lysosomes and acidify ( Martinez et al., 2011 ). While it has been argued that LC3 family proteins play an important role in facilitating this lysosomal fusion, details about the vesicle fusion mechanism remain obscure ( Martinez et al., 2015 ; McEwan et al., 2015 ; Nguyen and Yates, 2021 ).…”

Emerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis

“…Membrane fusion generally takes place in a cycle that begins with (i) tethering (involves HOPS) to bring late phagosomes and late lysosomes closer together to promote fusion, (ii) SNARE assembly, (iii) SNARE zippering, (iv) membrane fusion, (v) and SNARE disassembly and recycling [ 114 ]. There are 30 reported SNARE proteins to date; only a few specific SNARES form a stable trans-SNARE complex [ 96 , 114 ]. The SNARES for the membrane fusion of the late phagosome to the lysosome involves trans-SNARE Stx7-snap23-vam7/8 or Stx -Vtib-Stx8-Vamp 7/8 [ 114 ].…”

“…There are 30 reported SNARE proteins to date; only a few specific SNARES form a stable trans-SNARE complex [ 96 , 114 ]. The SNARES for the membrane fusion of the late phagosome to the lysosome involves trans-SNARE Stx7-snap23-vam7/8 or Stx -Vtib-Stx8-Vamp 7/8 [ 114 ]. The trans SNARE complex establishes a conformational change, thereby forming a cis SNARE complex that brings the two membranes together in a zippering process [ 115 ].…”

Branching Off: New Insight Into Lysosomes as Tubular Organelles

“…During the process of autophagy, for example, lysosomes receive cytosolic cargo via autophagosome delivery or direct uptake, and once cargo is within the lysosomal compartment, acid hydrolases activated by low pH digest the material ( Kaur and Debnath 2015 ; Ballabio and Bonifacino 2020 ; Butsch et al, 2021 ). In addition to destroying material originating from within the cell via autophagy, lysosomes receive and degrade material delivered from outside the cell via endocytosis and phagocytosis ( Luzio et al, 2009 ; Nguyen and Yates 2021 ). Beyond these digestive tasks, lysosomes also serve many non-degradative roles in the cell, including in nutrient sensing, intracellular sorting, metabolism, and signaling ( Settembre et al, 2013 ; Lim and Zoncu 2016 ; Perera and Zoncu 2016 ; Trivedi et al, 2020 ; Bouhamdani et al, 2021 ).…”