SLI-1 Cbl Inhibits the Engulfment of Apoptotic Cells in C. elegans through a Ligase-Independent Function

The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway, which includes the small GTPase CED-10 Rac and the cytoskeletal regulator ABI-1, acts to rearrange the cytoskeleton of the engulfing cell. The CED-10 Rac pathway is also required for proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. The second pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Cbl, the mammalian homolog of the C. elegans E3 ubiquitin ligase and adaptor protein SLI-1, interacts with Rac and Abi2 and modulates the actin cytoskeleton, suggesting it might act in engulfment. Our genetic studies indicate that SLI-1 inhibits apoptotic cell engulfment and DTC migration independently of the CED-10 Rac and CED-1 pathways. We found that the RING finger domain of SLI-1 is not essential to rescue the effects of SLI-1 deletion on cell migration, suggesting that its role in this process is ubiquitin ligase-independent. We propose that SLI-1 opposes the engulfment of apoptotic cells via a previously unidentified pathway.

凋亡细胞的吞噬作用对于正常后生动物发育与组织重塑不可或缺。在秀丽隐杆线虫（Caenorhabditis elegans）中，两条保守且存在部分功能冗余的平行通路参与细胞尸体的吞噬过程。其中一条通路包含小GTP酶CED-10 Rac与细胞骨架调控因子ABI-1，其核心功能是重排吞噬细胞的细胞骨架；CED-10 Rac通路同时也是秀丽隐杆线虫性腺发育过程中远端尖端细胞（DTCs）正常迁移所必需的信号途径。第二条通路包含受体酪氨酸激酶CED-1，该通路可能通过招募膜结构以延伸吞噬细胞的细胞膜表面。
Cbl是秀丽隐杆线虫E3泛素连接酶兼衔接蛋白SLI-1的哺乳动物同源蛋白，可与Rac及Abi2相互作用并调控肌动蛋白细胞骨架，这提示其可能参与细胞吞噬过程。
本研究的遗传学实验结果表明，SLI-1能够独立于CED-10 Rac与CED-1通路，抑制凋亡细胞的吞噬作用以及DTC的迁移。
我们进一步发现，SLI-1的环指结构域对于挽救SLI-1缺失所导致的细胞迁移异常并非必需，这意味着SLI-1在此过程中的调控功能不依赖于泛素连接酶活性。
综上，我们提出SLI-1可通过一条此前未被阐明的信号通路拮抗凋亡细胞的吞噬作用。