Requirement for a Drosophila E3-Ubiquitin Ligase in Phagocytosis of Apoptotic Cells

Silva, Elizabeth; Au-Yeung, Hiu Wan; Goethem, Emeline Van; Burden, Jemima J.; Franc, Nathalie C.

doi:10.1016/j.immuni.2007.08.016

Cited by 51 publications

(65 citation statements)

References 52 publications

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“…Similar results were obtained with DD1; hmlGAL4 and DD1; hmlGAL4; UAS-ICE. colleagues showed that a gain-of-function allele of Toll (Toll10B) was able to induce spz expression in the absence of immune challenge (Senger et al, 2006). We expressed the same Toll allele through a UAS construct in the haemocytes using crq-GAL4 (Silva et al, 2007). This is a GAL4 driver expressed in the pattern of croquemort, a gene coding for a macrophage-specific receptor of apoptotic corpses (Franc et al, 1996).…”

Section: Drs-gfp Induction In the Fat Body Is Influenced By The Absenmentioning

confidence: 99%

Toll-dependent antimicrobial responses inDrosophilalarval fat body require Spätzle secreted by haemocytes

Shia

Glittenberg

Thompson

et al. 2009

Journal of Cell Science

128

123

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In Drosophila, the humoral response characterised by the synthesis of antimicrobial peptides (AMPs) in the fat body (the equivalent of the mammalian liver) and the cellular response mediated by haemocytes (blood cells) engaged in phagocytosis represent two major reactions that counter pathogens. Although considerable analysis has permitted the elucidation of mechanisms pertaining to the two responses individually, the mechanism of their coordination has been unclear. To characterise the signals with which infection might be communicated between blood cells and fat body, we ablated circulating haemocytes and defined the parameters of AMP gene activation in larvae. We found that targeted ablation of blood cells influenced the levels of AMP gene expression in the fat body following both septic injury and oral infection. Expression of the AMP gene drosomycin (a Toll target) was blocked when expression of the Toll ligand Spätzle was knocked down in haemocytes. These results show that in larvae, integration of the two responses in a systemic reaction depend on the production of a cytokine (spz), a process that strongly parallels the mammalian immune response.

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Section: Drs-gfp Induction In the Fat Body Is Influenced By The Absenmentioning

confidence: 99%

Toll-dependent antimicrobial responses inDrosophilalarval fat body require Spätzle secreted by haemocytes

Shia

Glittenberg

Thompson

et al. 2009

Journal of Cell Science

128

123

View full text Add to dashboard Cite

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“…It remains to be seen if key engulfment receptors such as Draper and Croquemort in Drosophila, or their mammalian counterparts are ubiquitylated. However, it is noteworthy that Pall-deficient macrophages still possess the ability to take up AcLDL via the scavenger receptor pathway, further supporting the idea that Pall-SCF may function specifically in the context of apoptotic cell recognition by engulfment receptors 15 .…”

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confidence: 73%

“…Recently Nathalie Franc and colleagues have demonstrated for the first time a role for the SCF-ubiquitylation complex in the uptake of apoptotic cells by macrophages 15 . In this study, Drosophila embryos containing genomic deletions were screened for a failure to efficiently engulf apoptotic cells.…”

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confidence: 99%

“…In addition to identifying pall as a novel engulfment gene, Silva et al examined the role of Pall in the context of the SCF-ubiquitylation apparatus 15 . Through biochemical analyses it was shown that Pall interacts with SkpA via its F-box domain in S2 insect cells.…”

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confidence: 99%

“…It is notable that pall null embryonic macrophages can still engulf apoptotic cells (~1 corpse per macrophage compared to ~3 for wild-type), indicating partial redundancy in the system 15 . Still these data raise intriguing and important questions not addressed by this study: What is the role of the Ub-proteasomal pathway during engulfment and what are the substrates targeted by Pall?…”

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Pallbearer and friends: lending a hand in apoptotic cell clearance

Elliott

Ravichandran

2008

Trends in Cell Biology

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Engulfment and prompt removal of apoptotic cells occurs from embryogenesis throughout the lifespan of multi-cellular organisms. A new player, Pallbearer, has recently been identified in Drosophila as being important for efficient engulfment by macrophages. Pallbearer is a component of the SCF E3 ubiquitin ligase complex involved in ubiquitylation of proteins targeted for proteasomal degradation. This work provides the first link between the cellular processes of ubiquitylation/proteasomal degradation and the ability to efficiently clear apoptotic cells.The efficient engulfment and removal of apoptotic cells is important for tissue homeostasis and immunological self-tolerance 1 . Such engulfment is carried out by competent neighboring cells or by professional phagocytes, such as macrophages and immature dendritic cells. In recent years, the molecular underpinnings of this process have begun to be revealed through studies in the model organisms C. elegans and Drosophila, along with molecular and biochemical studies in mammalian cells and via knockout mice 2, 3 . Three key steps in the phagocytic removal of apoptotic cells are recognition, internalization and degradation. Apoptotic cells display several "eat-me" markers that serve as molecular cues for phagocyte recognition and to initiate engulfment via receptors on the phagocyte. The most prominent of these "eat-me" signals is the exposure of phosphatidylserine (PS) on the outer leaflet of the plasma membrane 4 . Multiple modes of PS recognition have been defined, including the recent identification of direct PS-binding receptors Bai1, Tim4 and Stabilin-2 5-7 . Upon encountering the apoptotic target, rearrangement of the actin cytoskeleton occurs in the phagocyte, driven primarily by the Rho GTPase Rac 8 . This leads to the formation of an actin-rich phagocytic cup that envelops the apoptotic cell. After internalization, the corpse proceeds through the phagolysosomal pathway where the remnants of the apoptotic cell are degraded and processed. Although the degradative step remains poorly understood, this process is clearly important for antigen presentation and protein recycling and may impact the efficiency of corpse engulfment 9, 10 .The post-translational modification of proteins by ubiquitylation has a well-documented role in targeting proteins for proteasomal degradation and regulation of numerous cellular processes including protein transport, cell cycle progression, DNA repair and inflammation [11][12][13] . Ubiquitylation is carried out through a series of enzymatic steps that results in the covalent attachment of the 8 kDa ubiquitin (Ub) protein to lysine residues on substrate proteins. The Ub-activating enzyme (E1) transfers Ub to Ub-conjugating enzymes (E2). The Ub-ligases (E3) bind to substrate proteins and promote transfer of the Ub from E2 to specific lysine residues on the target protein. Substrate specificity for ubiquitylation is determined by

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Keeping the CNS clear: Glial phagocytic functions in Drosophila

Kurant

2010

Glia

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Elimination of unwanted and potentially harmful matter is crucial for nervous system development and function. Glia are the main cleaners of the CNS that perform their function through engulfment and degradation of dying neurons and degenerating neuronal branches, developing excessive axons and synapses. Recent studies in Drosophila melanogaster have enhanced significantly our understanding of the phagocytic functions of glia and demonstrated that Drosophila provides an excellent model for investigating the molecular and cellular basis of glial phagocytosis. The current knowledge and great potential of this model, which is reviewed here, can open new directions in mammalian glial biology.

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Requirement for a Drosophila E3-Ubiquitin Ligase in Phagocytosis of Apoptotic Cells

Cited by 51 publications

References 52 publications

Toll-dependent antimicrobial responses inDrosophilalarval fat body require Spätzle secreted by haemocytes

Toll-dependent antimicrobial responses inDrosophilalarval fat body require Spätzle secreted by haemocytes

Pallbearer and friends: lending a hand in apoptotic cell clearance

Keeping the CNS clear: Glial phagocytic functions in Drosophila

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