Department of Immunology and Microbial Science and Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Medical Research Council Laboratory for Molecular Cell Biology, London WC1E 6BT, UK.
Dev Cell. 2015 Jan 12;32(1):19-30. doi: 10.1016/j.devcel.2014.11.015. Epub 2014 Dec 18.
Clearance of apoptotic cells (efferocytosis) is achieved through phagocytosis by professional or amateur phagocytes. It is critical for tissue homeostasis and remodeling in all animals. Failure in this process can contribute to the development of inflammatory autoimmune or neurodegenerative diseases. We found previously that the PALL-SCF E3-ubiquitin ligase complex promotes apoptotic cell clearance, but it remained unclear how it did so. Here we show that the F-box protein PALL interacts with phosphorylated ribosomal protein S6 (RpS6) to promote its ubiquitylation and proteasomal degradation. This leads to RAC2 GTPase upregulation and activation and F-actin remodeling that promotes efferocytosis. We further show that the specific role of PALL in efferocytosis is driven by its apoptotic cell-induced nuclear export. Finding a role for RpS6 in the negative regulation of efferocytosis provides the opportunity to develop new strategies to regulate this process.
凋亡细胞（胞噬作用）的清除是通过专业或业余吞噬细胞的吞噬作用来实现的。它对于所有动物的组织平衡和重塑都至关重要。该过程的失败可能导致炎症性自身免疫或神经退行性疾病的发展。我们之前发现 PALL-SCF E3-泛素连接酶复合物可促进凋亡细胞的清除，但尚不清楚其具体作用机制。在这里，我们表明 F-box 蛋白 PALL 与磷酸化核糖体蛋白 S6（RpS6）相互作用，促进其泛素化和蛋白酶体降解。这导致 RAC2 GTP 酶的上调和激活以及 F-肌动蛋白的重塑，从而促进胞噬作用。我们进一步表明，PALL 在胞噬作用中的特定作用是由其诱导的凋亡细胞的核输出驱动的。发现 RpS6 在胞噬作用的负调控中的作用为开发调控该过程的新策略提供了机会。
