Phagosome maturation during the removal of apoptotic cells: receptors lead the way

Zhou, Zheng; Yu, Xiaomeng

doi:10.1016/j.tcb.2008.08.002

Cited by 62 publications

(66 citation statements)

References 97 publications

(225 reference statements)

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“…that are recruited to phagosomes at different stages during their maturation Zhou and Yu, 2008). We found that TBC-2 was transiently recruited to phagosomes at a similar stage to RAB-5, which was followed by the recruitment of RAB-7 (Fig.…”

Section: Research Articlementioning

confidence: 64%

“…The resulting intracellular vesicles containing ingested apoptotic cells, termed phagosomes, undergo a series of maturation steps leading to the destruction of cell corpses. Although the specific factors and mechanisms controlling maturation of apoptotic-cell-containing phagosomes are not well understood, recent studies in C. elegans indicate that cell corpse clearance through phagosome maturation follows a general path that requires similar components and cellular events to that of phagosomes carrying opsonized particles or microorganisms Vieira et al, 2002;Zhou and Yu, 2008). For example, Rab GTPases, the key regulators of endocytic transport and maturation of phagosomes with ingested opsonized cells or microbes, are also found to play important roles in the maturation of phagosomes containing apoptotic cells in both mammals and C. elegans Kitano et al, 2008;Lu et al, 2008;Mangahas et al, 2008;Yu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…RAB5 is recruited transiently to the newly formed phagosomes in intact macrophages, and it is essential for the fusion between isolated sorting endosomes and purified nascent phagosomes in a cell-free system (Desjardins et al, 1994;Desjardins et al, 1997;Henry et al, 2004;Jahraus et al, 1998;Roberts et al, 2000;Vieira et al, 2002). Moreover, RAB5/RAB-5 is found to be transiently associated with apoptotic-cell-containing phagosomes at an early stage and is required for phagosome maturation and apoptotic cell degradation in mammals and C. elegans Kitano et al, 2008;Zhou and Yu, 2008).…”

Section: Introductionmentioning

confidence: 99%

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C. elegansRab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5

Zou

Zhao

et al. 2009

Development

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During apoptosis, dying cells are quickly internalized by neighboring cells or phagocytes, and are enclosed in phagosomes that undergo a maturation process to generate the phagoslysosome, in which cell corpses are eventually degraded. It is not well understood how apoptotic cell degradation is regulated. Here we report the identification and characterization of the C. elegans tbc-2 gene, which is required for the efficient degradation of cell corpses. tbc-2 encodes a Rab GTPase activating protein (GAP) and its loss of function affects several events of phagosome maturation, including RAB-5 release, phosphatidylinositol 3-phosphate dynamics, phagosomal acidification, RAB-7 recruitment and lysosome incorporation, which leads to many persistent cell corpses at various developmental stages. Intriguingly, the persistent cell corpse phenotype of tbc-2 mutants can be suppressed by reducing gene expression of rab-5, and overexpression of a GTP-locked RAB-5 caused similar defects in phagosome maturation and cell corpse degradation. We propose that TBC-2 functions as a GAP to cycle RAB-5 from an active GTP-bound to an inactive GDP-bound state, which is required for maintaining RAB-5 dynamics on phagosomes and serves as a switch for the progression of phagosome maturation.

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Section: Research Articlementioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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C. elegansRab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5

Zou

Zhao

et al. 2009

Development

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“…The degradation of ingested cellular material involves phagosome maturation through homotypic and heterotypic fusion of early endosomes, late endosomes and lysosomes (Zhou and Yu, 2008). The classical markers employed for the discrimination of these different phases are Ras-related protein 5 (Rab5), a small GTPase associated with early phagosomes (Kinchen et al, 2008;Desjardins et al, 1994), and annexin I (Anx1) or lysosomal-associated membrane protein 1 (LAMP1), two proteins that are utilized to show later phagosomal stages and phagosomes after lysosomal fusion, respectively (May and Machesky, 2001;Alvarez-Dominguez et al, 1997;Tjelle et al, 2000).…”

Section: Internalized Tumor Cell Fragments Colocalize With Phagosome mentioning

confidence: 99%

Phagocytosis of dying tumor cells by human peritoneal mesothelial cells

Wagner

Lindau

Ripper

et al. 2011

Journal of Cell Science

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SummaryPeritoneal carcinomatosis is an advanced form of metastatic disease characterized by cancer cell dissemination onto the peritoneum. It is commonly observed in ovarian and colorectal cancers and is associated with poor patient survival. Novel therapies consist of cytoreductive surgery in combination with intraperitoneal chemotherapy, aiming at tumor cell death induction. The resulting dying tumor cells are considered to be eliminated by professional as well as semi-professional phagocytes. In the present study, we have identified a hitherto unknown type of 'amateur' phagocyte in this environment: human peritoneal mesothelial cells (HMCs). We demonstrate that HMCs engulf corpses of dying ovarian and colorectal cancer cells, as well as other types of apoptotic cells. Flow cytometric, confocal and electron microscopical analyses revealed that HMCs ingest dying cell fragments in a dose-and timedependent manner and the internalized material subsequently traffics into late phagolysosomes. Regarding the mechanisms of prey cell recognition, our results show that HMCs engulf apoptotic corpses in a serum-dependent and -independent fashion and quantitative real-time PCR (qRT-PCR) analyses revealed that diverse opsonin receptor systems orchestrating dying cell clearance are expressed in HMCs at high levels. Our data strongly suggest that HMCs contribute to dying cell removal in the peritoneum, and future studies will elucidate in what manner this influences tumor cell dissemination and the antitumor immune response.

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“…S2). Moreover, Rab5 GTPase, which has recently been shown to be crucial in macrophages in the final maturation process before degradation by the lysosomal enzymes occurs (Zhou and Yu, 2008), is expressed at normal levels in the Nuc1 RPE (supplementary material Fig. S2).…”

Section: Discussionmentioning

confidence: 99%

Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat

Zigler

Zhang

Grebe

et al. 2011

Journal of Cell Science

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Phagocytosis of the shed outer segment discs of photoreceptors is a major function of the retinal pigmented epithelium (RPE). We demonstrate for the first time that βA3/A1-crystallin, a major structural protein of the ocular lens, is expressed in RPE cells. Further, by utilizing the Nuc1 rat, in which the βA3/A1-crystallin gene is mutated, we show that this protein is required by RPE cells for proper degradation of outer segment discs that have been internalized in phagosomes. We also demonstrate that in wild-type RPE, βA3/A1-crystallin is localized to the lysosomes. However, in the Nuc1 RPE, βA3/A1-crystallin fails to translocate to the lysosomes, perhaps because misfolding of the mutant protein masks sorting signals required for proper trafficking. The digestion of phagocytized outer segments requires a high level of lysosomal enzyme activity, and cathepsin D, the major enzyme responsible for proteolysis of the outer segments, is decreased in mutant RPE cells. Interestingly, our results also indicate a defect in the autophagy process in the Nuc1 RPE, which is probably also linked to impaired lysosomal function, because phagocytosis and autophagy might share common mechanisms in degradation of their targets. βA3/A1-crystallin is a novel lysosomal protein in RPE, essential for degradation of phagocytosed material.

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Phagosome maturation during the removal of apoptotic cells: receptors lead the way

Cited by 62 publications

References 97 publications

C. elegansRab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5

C. elegansRab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5

Phagocytosis of dying tumor cells by human peritoneal mesothelial cells

Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat

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