SLI-1 Cbl inhibits the engulfment of apoptotic cells in C. elegans through a ligase-independent function.
SLI-1 Cbl inhibits the engulfment of apoptotic cells in C. elegans through a ligase-independent function.
复制标题
DOI：
10.1371/journal.pgen.1003115
复制
发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Hurwitz ME
中科院分区：
文献类型：
--
作者：
Anderson C;Zhou S;Sawin E;Horvitz HR;Hurwitz ME
凋亡细胞的吞噬是正常后生动物发育和组织重塑所必需的。在秀丽隐杆线虫中，两个平行且部分冗余的保守途径在细胞尸体吞噬中起作用。一种途径，包括小的GTCED-10 Rac和细胞骨架调节因子ABI-1，用于重新排列吞噬细胞的细胞骨架。CED-10 Rac通路也是C.秀丽隐翅虫性腺第二种途径包括受体酪氨酸激酶CED-1，并且可能招募膜以扩展吞噬细胞的表面。Cbl是C. E3泛素连接酶和接头蛋白SLI-1与Rac和Abi 2相互作用并调节肌动蛋白细胞骨架，表明它可能在吞噬中起作用。我们的遗传学研究表明，SLI-1抑制凋亡细胞吞噬和DTC迁移的CED-10 Rac和CED-1途径独立。我们发现SLI-1的RING指结构域对于拯救SLI-1缺失对细胞迁移的影响并不是必需的，这表明它在这个过程中的作用是不依赖于泛素连接酶的。我们认为SLI-1通过一种以前未发现的途径对抗凋亡细胞的吞噬。细胞死亡是生物体发育的正常部分。当细胞死亡时，其他细胞吞噬它们。在蛔虫C.在elegans中，吞噬是通过一种重排肌动蛋白细胞骨架的途径和另一种募集膜的途径来促进的。它们一起导致死亡细胞周围细胞延伸的形成。值得注意的是，关于吞噬是如何被抑制的知之甚少。也促进细胞迁移的细胞骨架调节途径包括CED-10和ABI-1，它们分别是肌动蛋白调节剂Rac和Abi蛋白的同系物。在哺乳动物中，c-Cbl原癌基因与Rac和Abi2相互作用，并已被证明可调节肌动蛋白细胞骨架，因此我们测试了C. Cbl的elegans同源物SLI-1调节吞噬和细胞迁移。我们发现SLI-1抑制这两个过程。我们的分析进一步表明，SLI-1不通过抑制其他已知的吞噬蛋白发挥作用。cbl蛋白具有泛素连接酶结构域，通过该结构域，cbl蛋白靶向蛋白进行破坏或隔离。Cbl蛋白的大多数已知功能都需要该结构域，但我们发现SLI-1并不需要它来阻止吞噬和细胞迁移。我们认为SLI-1通过一种以前未发现的途径抑制吞噬和细胞迁移。
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. Cell death is a normal part of organismal development. When cells die, other cells engulf them. In the roundworm C. elegans, engulfment is facilitated by one pathway that rearranges the actin cytoskeleton and another that recruits membrane. Together they cause the formation of cellular extensions that surround the dead cell. Notably, little is known about how engulfment is inhibited. The cytoskeletal regulatory pathway, which also promotes cell migration, includes CED-10 and ABI-1, homologs of the actin regulators Rac and the Abi proteins, respectively. In mammals, the c-Cbl proto-oncogene interacts with Rac and Abi2 and has been shown to regulate the actin cytoskeleton, so we tested whether the C. elegans homolog of Cbl, SLI-1, regulates engulfment and cell migration. We found that SLI-1 inhibits both processes. Our analysis further showed that SLI-1 does not function by inhibiting other known engulfment proteins. Cbl proteins have ubiquitin ligase domains through which they target proteins for destruction or sequestration. Most of the known functions of Cbl proteins require that domain, but we found that SLI-1 did not require it to block engulfment and cell migration. We propose that SLI-1 inhibits engulfment and cell migration through a previously unidentified pathway.
登录
查看更多内容
影响因子：
9.8
作者：
Hurwitz ME;Vanderzalm PJ;Bloom L;Goldman J;Garriga G;Horvitz HR
通讯作者：
Horvitz HR
影响因子：
4.8
作者：
Hu, JJ;Hubbard, SR
通讯作者：
Hubbard, SR
影响因子：
64.8
作者：
Hoeppner, DJ;Hengartner, MO;Schnabel, R
通讯作者：
Schnabel, R
影响因子：
2.7
作者：
HIRSH, D;OPPENHEIM, D;KLASS, M
通讯作者：
KLASS, M
影响因子：
16
作者：
Ceol, CJ;Horvitz, HR
通讯作者：
Horvitz, HR