scholarly journals The small GTPase RAB-35 facilitates the initiation of phagosome maturation and acts as a robustness factor for apoptotic cell clearance

Small GTPases ◽  
2019 ◽  
pp. 1-14
Author(s):  
Ryan Haley ◽  
Zheng Zhou
Keyword(s):  
Apoptotic Cell ◽  
Small Gtpase ◽  
Phagosome Maturation ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance

scholarly journals RAB-35 aids apoptotic cell clearance by regulating cell corpse recognition and phagosome maturation

2018 ◽  
Author(s):  
Ryan C. Haley ◽  
Ying Wang ◽  
Zheng Zhou
Keyword(s):  
Apoptotic Cell ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Apoptotic Cells ◽  
Rab Gtpases ◽  
Phagosome Maturation ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Early Endosomes ◽  
Cell Corpse

AbstractIn metazoans, apoptotic cells are swiftly engulfed by phagocytes and degraded inside phagosomes. Multiple small GTPases in the Rab family are known to function in phagosome maturation by regulating vesicle trafficking. We discovered rab-35 as a new gene important for apoptotic cell clearance using an RNAi screen targeting putative Rab GTPases in Caenorhabditis elegans. We further identified TBC-10 as a putative GTPase-activating protein (GAP), and FLCN-1 and RME-4 as two putative Guanine Nucleotide Exchange Factors (GEFs), for RAB-35. RAB-35 function was found to be required for the incorporation of early endosomes to phagosomes and for the timely degradation of apoptotic cell corpses. More specifically, RAB-35 facilitates the switch of phagosomal membrane phosphatidylinositol species from PtdIns(4,5)P2 to PtdIns(3)P and promotes the recruitment of the small GTPase RAB-5 to phagosomal surfaces, processes that are essential for phagosome maturation. Interestingly, we observed that CED-1 performs these same functions, and to a much larger extent than RAB-35. Remarkably, in addition to cell corpse degradation, RAB-35 also facilitates the recognition of cell corpses independently of the CED-1 and CED-5 pathways. RAB-35 localizes to extending pseudopods and is further enriched on nascent phagosomes, consistent with its dual roles in regulating cell corpse-recognition and phagosome maturation. Epistasis analyses indicate that rab-35 represents a novel third genetic pathway that acts in parallel to both of the canonical ced-1/6/7 and ced-2/5/10/12 engulfment pathways. We propose that RAB-35 acts as a robustness factor, leading a pathway that aids the canonical pathways for the engulfment and degradation of apoptotic cells.

scholarly journals GOP-1 promotes apoptotic cell degradation by activating the small GTPase Rab2 in C. elegans

2017 ◽  
Vol 216 (6) ◽  
pp. 1775-1794 ◽  
Author(s):  
Jianhua Yin ◽  
Yaling Huang ◽  
Pengfei Guo ◽  
Siqi Hu ◽  
Sawako Yoshina ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Small Gtpase ◽  
Dense Core Vesicle ◽  
Rab Gtpases ◽  
Membrane Recruitment ◽  
C Elegans ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Cell Corpse

Apoptotic cells generated by programmed cell death are engulfed by phagocytes and enclosed within plasma membrane–derived phagosomes. Maturation of phagosomes involves a series of membrane-remodeling events that are governed by the sequential actions of Rab GTPases and lead to formation of phagolysosomes, where cell corpses are degraded. Here we identified gop-1 as a novel regulator of apoptotic cell clearance in Caenorhabditis elegans. Loss of gop-1 affects phagosome maturation through the RAB-5–positive stage, causing defects in phagosome acidification and phagolysosome formation, phenotypes identical to and unaffected by loss of unc-108, the C. elegans Rab2. GOP-1 transiently associates with cell corpse–containing phagosomes, and loss of its function abrogates phagosomal association of UNC-108. GOP-1 interacts with GDP-bound and nucleotide-free UNC-108/Rab2, disrupts GDI-UNC-108 complexes, and promotes activation and membrane recruitment of UNC-108/Rab2 in vitro. Loss of gop-1 also abolishes association of UNC-108 with endosomes, causing defects in endosome and dense core vesicle maturation. Thus, GOP-1 is an activator of UNC-108/Rab2 in multiple processes.

CD36-mediated apoptotic cell clearance in SLE

Lupus ◽  
2001 ◽  
Vol 10 (9) ◽  
pp. 656-657 ◽  
Author(s):  
A P Cairns ◽  
A D Crockard ◽  
A L Bell
Keyword(s):  
Apoptotic Cell ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance

scholarly journals Chemokines as phosphatidylserine-bound ‘find-me’ signals in apoptotic cell clearance

2020 ◽  
Author(s):  
Sergio M. Pontejo ◽  
Philip M. Murphy
Keyword(s):  
Extracellular Vesicles ◽  
Chemokine Receptors ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Anionic Phospholipid ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Cell Plasma ◽  
Signal Activity ◽  
Dying Cells

AbstractChemokines are positively charged cytokines that attract leukocytes by binding to anionic glycosaminoglycans (GAGs) on endothelial cells for efficient presentation to leukocyte G protein-coupled receptors (GPCRs). The atypical chemokine CXCL16 has been reported to also bind the anionic phospholipid phosphatidylserine (PS), but the biological relevance of this interaction remains poorly understood. Here we demonstrate that PS binding is in fact a widely shared property of chemokine superfamily members that, like GAG binding, induces chemokine oligomerization. PS is an essential phospholipid of the inner leaflet of the healthy cell plasma membrane but it is exposed in apoptotic cells to act as an ‘eat-me’ signal that promotes engulfment of dying cells by phagocytes. We found that chemokines can bind PS in pure form as well as in the context of liposomes and on the surface of apoptotic cells and extracellular vesicles released by apoptotic cells, which are known to act as ‘find-me’ signals that chemoattract phagocytes during apoptotic cell clearance. Importantly, we show that GAGs are severely depleted from the surface of apoptotic cells and that extracellular vesicles extracted from apoptotic mouse thymus bind endogenous thymic chemokines and activate cognate chemokine receptors. Together these results indicate that chemokines tethered to surface-exposed PS may be responsible for the chemotactic and find-me signal activity previously attributed to extracellular vesicles, and that PS may substitute for GAGs as the anionic scaffold that regulates chemokine oligomerization and presentation to GPCRs on the GAG-deficient membranes of apoptotic cells and extracellular vesicles. Here, we present a new mechanism by which extracellular vesicles, currently recognized as essential agents for intercellular communication in homeostasis and disease, can transport signaling cytokines.

scholarly journals Overexposure to apoptosis via disrupted glial specification perturbs Drosophila macrophage function and reveals roles of the CNS during injury

2020 ◽  
Author(s):  
Emma Louise Armitage ◽  
Hannah Grace Roddie ◽  
Iwan Robert Evans
Keyword(s):  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Calcium Waves ◽  
Apoptotic Cells ◽  
Phagocytic Cells ◽  
Macrophage Function ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Wound Responses

AbstractApoptotic cell clearance by phagocytes is a fundamental process during development, homeostasis and the resolution of inflammation. However, the demands placed on phagocytic cells such as macrophages by this process, and the limitations these interactions impose on subsequent cellular behaviours are not yet clear. Here we seek to understand how apoptotic cells affect macrophage function in the context of a genetically-tractable Drosophila model in which macrophages encounter excessive amounts of apoptotic cells. We show that loss of the glial transcription factor repo, and corresponding removal of the contribution these cells make to apoptotic cell clearance, causes macrophages in the developing embryo to be challenged with large numbers of apoptotic cells. As a consequence, macrophages become highly vacuolated with cleared apoptotic cells and their developmental dispersal and migration is perturbed. We also show that the requirement to deal with excess apoptosis caused by a loss of repo function leads to impaired inflammatory responses to injury. However, in contrast to migratory phenotypes, defects in wound responses cannot be rescued by preventing apoptosis from occurring within a repo mutant background. In investigating the underlying cause of these impaired inflammatory responses, we demonstrate that wound-induced calcium waves propagate into surrounding tissues, including neurons and glia of the ventral nerve cord, which exhibit striking calcium waves on wounding, revealing a previously unanticipated contribution of these cells during responses to injury. Taken together these results demonstrate important insights into macrophage biology and how repo mutants can be used to study macrophage-apoptotic cell interactions in the fly embryo.Furthermore, this work shows how these multipurpose cells can be ‘overtasked’ to the detriment of their other functions, alongside providing new insights into which cells govern macrophage responses to injury in vivo.

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