The adaptor protein GULP promotes Jedi-1–mediated phagocytosis through a clathrin-dependent mechanism

Sullivan, Chelsea S.; Scheib, Jami L.; Ma, Zhiyuan; Dang, Rajan P.; Schafer, Johanna M.; Hickman, F. Edward; Brodsky, Frances M.; Ravichandran, Kodi S.; Carter, Bruce D.

doi:10.1091/mbc.e13-11-0658

Cited by 18 publications

(14 citation statements)

References 40 publications

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“…Therefore, we asked whether megf6 takes on this role in planarians, which lack a MEGF10/11 ortholog. Interestingly, planarians do have orthologs of many of the regulators of phagocytosis downstream of Draper/Ced-1/MEGF10/11 in flies and C. elegans, including ABCA1, shark, ELMO, and gulp [36][37][38][39]. However, upon RNAi knockdown we found that none of these genes reproduced the knockdown phenotypes of megf6 (S3 Fig).…”

Section: Megf6 Is An Uncharacterized Gene Conserved In Metazoansmentioning

confidence: 91%

Planarian EGF repeat-containing genes megf6 and hemicentin are required to restrict the stem cell compartment

2020

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The extracellular matrix (ECM) is important for maintaining the boundaries between tissues. This role is particularly critical in the stem cell niche, as pre-neoplastic or cancerous stem cells must pass these boundaries in order to invade into the surrounding tissue. Here, we examine the role of the ECM as a regulator of the stem cell compartment in the planarian Schmidtea mediterranea, a highly regenerative, long-lived organism with a large population of adult stem cells. We identify two EGF repeat-containing genes, megf6 and hemicentin, with identical knockdown phenotypes. We find that megf6 and hemicentin are needed to maintain the structure of the basal lamina, and in the absence of either gene, pluripotent stem cells migrate ectopically outside of their compartment and hyper-proliferate, causing lesions in the body wall muscle. These muscle lesions and ectopic stem cells are also associated with ectopic gut branches, which protrude from the normal gut towards the dorsal side of the animal. Interestingly, both megf6 and hemicentin knockdown worms are capable of regenerating tissue free of both muscle lesions and ectopic cells, indicating that these genes are dispensable for regeneration. These results provide insight into the role of planarian ECM in restricting the stem cell compartment, and suggest that signals within the compartment may act to suppress stem cell hyperproliferation. expressed in different cell populations, we find that both are required to maintain the epithelial basal lamina. In the absence of either gene, stem cells can escape their compartment and migrate towards the skin of the animal, where they divide at an accelerated rate and cause lesions in the muscle. These results show that the extracellular matrix plays a role in limiting the boundaries of the stem cell compartment. megf6 and hemicentin restrict the planarian stem cell niche PLOS Genetics | https://doi.

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Section: Megf6 Is An Uncharacterized Gene Conserved In Metazoansmentioning

confidence: 91%

Planarian EGF repeat-containing genes megf6 and hemicentin are required to restrict the stem cell compartment

2020

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“…The protein markers chosen for analysis here have been used to identify a variety of cells with phagocytic activity, including cells of the monocyte-macrophage lineage [19–22]. To our knowledge their expression has not been described in mesenchymal progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Enhanced phagocytic capacity endows chondrogenic progenitor cells with a novel scavenger function within injured cartilage

Zhou

Zhang

Buckwalter

et al. 2016

Osteoarthritis and Cartilage

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Objective Articular cartilage harbors chondrogenic progenitor cells (CPCs), a population that responds chemotactically to cell death. Because this behavior is reminiscent of macrophages, we hypothesized that CPCs have macrophage-like capabilities for scavenging cell and tissue debris through phagocytosis. Design CPCs, chondrocytes, synoviocytes, and macrophages were cultured with fluorophore-labeled chondrocyte debris for 3, 6, 12, or 24 hours. Debris internalization was quantified by confocal microscopy and flow cytometry. Confocal microscopy was also used to test CPCs and chondrocytes for uptake of fluorophore-labeled fibronectin fragments (Fn-fs), a form of extracellular matrix debris. Lysosome activity and mass in CPCs and chondrocytes were measured using fluorescent probes. The relative expression of phagocytosis-related genes and proteins was evaluated by polymerase chain reaction (PCR) and immunoblotting, respectively. Pulse-chase experiments were performed to determine if the debris internalized by CPCs and chondrocytes was cleared, and if clearance was affected by a cathepsin B inhibitor. Results More macrophages, synoviocytes, and CPCs internalized cell debris than chondrocytes at all time points. While uptake remained flat in chondrocytes at ~10%, in the other cell types it peaked at more than 60% after 12 – 24 hours. Relative to chondrocytes, CPCs showed significantly higher rates of Fn-fs engulfment, greater lysosome activity and mass, and over-expressed phagocytosis-related genes and proteins. Pulse-chase experiments revealed time- and cathepsin B- dependent clearance of cell debris in CPCs, but not in chondrocytes. Conclusions CPCs phagocytized cell and matrix debris much more efficiently than chondrocytes, supporting the hypothesis that they play a macrophage-like role in injured cartilage.

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“…Chronic obstructive pulmonary disease (COPD) severity was defined in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification: based on post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) in patients with FEV 1 /forced vital capacity (FVC) < 0.7, GOLGD I (mild) is FEV 1 80% predicted, GOLD II (moderate) is 50% FEV 1 < 80% predicted, GOLD III (severe) is 30% FEV 1 < 50% predicted, and GOLD IV (very severe) is FEV 1 < 30% predicted. considered to have a functional role in the phagocytic process, where it was identified in a screen for genes regulating the clearance of apoptotic cells [15,16,35,36]. GULP1, an apoptosisassociated gene was suggested to play a role in the pathogenesis of some human disease such as arthritis and schizophrenia [17,18].…”

Section: Variablesmentioning

confidence: 99%

Expression of GULP1 in bronchial epithelium is associated with the progression of emphysema in chronic obstructive pulmonary disease

Datta

Nam

Hayashi

et al. 2017

Respiratory Medicine

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The adaptor protein GULP promotes Jedi-1–mediated phagocytosis through a clathrin-dependent mechanism

Cited by 18 publications

References 40 publications

Planarian EGF repeat-containing genes megf6 and hemicentin are required to restrict the stem cell compartment

Planarian EGF repeat-containing genes megf6 and hemicentin are required to restrict the stem cell compartment

Enhanced phagocytic capacity endows chondrogenic progenitor cells with a novel scavenger function within injured cartilage

Expression of GULP1 in bronchial epithelium is associated with the progression of emphysema in chronic obstructive pulmonary disease

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