bfc, a novel serpent co-factor for the expression of croquemort, regulates efferocytosis in Drosophila melanogaster

摘要

Efferocytosis is the process by which phagocytes recognize, engulf, and digest (or clear) apoptotic cells during development. Impaired efferocytosis is associated with developmental defects and autoimmune diseases. In Drosophila melanogaster , recognition of apoptotic cells requires phagocyte surface receptors, including the scavenger receptor CD36-related protein, Croquemort (Crq, encoded by crq ). In fact, Crq expression is upregulated in the presence of apoptotic cells, as well as in response to excessive apoptosis. Here, we identified a novel gene bfc ( booster for croquemort ), which plays a role in efferocytosis, specifically the regulation of the crq expression. We found that Bfc protein interacts with the zinc finger domain of the GATA transcription factor Serpent (Srp), to enhance its direct binding to the crq promoter; thus, they function together in regulating crq expression and efferocytosis. Overall, we show that Bfc serves as a Srp co-factor to upregulate the transcription of the crq encoded receptor, and consequently boosts macrophage efferocytosis in response to excessive apoptosis. Therefore, this study clarifies how phagocytes integrate apoptotic cell signals to mediate efferocytosis. Author summary The swift removal of apoptotic cells by specialized cells such as macrophages (a subtype of white blood cells), is a critical event in shaping tissues during the development of all multicellular organisms, from worms to humans. Defects in the removal of dying cells, a process known as the clearance of apoptotic cells (ACs), can contribute to the development of autoimmune disorders such as systemic Lupus erythematosus (SLE) and neurodegenerative diseases like Alzheimer’s disease. Croquemort (Crq), a Drosophila CD36-related receptor, is required for the recognition and engulfment of ACs in macrophages. In this study, via transcriptomic analysis and RNAi screening, we discovered 12 genes required for the clearance of ACs in macrophage-like S2 cells in Drosophila . In particular, we identified a novel gene, bfc ( booster for croquemort ), involved in apoptotic cell clearance via the specific regulation of the crq transcriptional expression. We demonstrate that the GATA transcription factor Serpent (Srp) directly binds to the crq promoter, while Bfc strengthens this binding via its interaction with the Srp zinc finger domain. Therefore, we propose a model in which Bfc cooperates with Srp to enhance the expression of crq and subsequently induce apoptotic cell clearance in Drosophila melanogaster .