Abl kinase inhibits the engulfment of apoptotic [corrected] cells in Caenorhabditis elegans.
Abl kinase inhibits the engulfment of apoptotic [corrected] cells in Caenorhabditis elegans.
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DOI：
10.1371/journal.pbio.1000099
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发表时间：
2009-04-28
期刊：
影响因子：
9.8
通讯作者：
Horvitz HR
中科院分区：
文献类型：
--
作者：
Hurwitz ME;Vanderzalm PJ;Bloom L;Goldman J;Garriga G;Horvitz HR
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。一种途径包括衔接蛋白CED-2 CrkII和小的GTP酶CED-10 Rac，并用于重新排列吞噬细胞的细胞骨架。另一个途径包括受体酪氨酸激酶CED-1，并可能募集膜以延伸吞噬细胞的表面。虽然已经确定了吞噬所需的许多成分，但对吞噬的抑制知之甚少。酪氨酸激酶Abl以多种方式调节哺乳动物和果蝇中的肌动蛋白细胞骨架。例如，Abl通过CrkII的磷酸化抑制细胞迁移。我们检测了ABL-1、C. Abl的elegans直系同源物，抑制凋亡细胞的CED-2 CrkII依赖性吞噬。我们的遗传学研究表明，ABL-1抑制凋亡细胞吞噬，但不是通过CED-2 CrkII，而是平行于两个已知的吞噬途径。CED-10 Rac通路也是C.秀丽隐翅虫性腺在CED-10 Rac通路突变体中，ABL-1功能的丧失部分恢复了正常的DTC迁移。我们发现ABI-1是C.哺乳动物Abi（Abl相互作用物）蛋白的elegans同源物，是凋亡细胞的吞噬和适当的DTC迁移所必需的。与Abl一样，Abi蛋白是细胞骨架调节剂。ABI-1与两个已知的吞噬途径平行作用，可能在ABL-1的下游。ABL-1和ABI-1在体外物理相互作用。我们提出ABL-1通过抑制ABI-1来对抗凋亡细胞的吞噬，该途径与两种已知的吞噬途径不同。细胞死亡或凋亡是动物发育的正常部分，死亡细胞被其他细胞吞噬和清除也是如此。在线虫秀丽隐杆线虫中，10个高度保守的蛋白质先前已被表征为它们在吞噬和细胞迁移中的作用，这两者都涉及细胞延伸的形成。然而，人们对吞噬是如何被抑制的知之甚少。在哺乳动物中，酪氨酸激酶Abl，其调节肌动蛋白细胞骨架，并且当错误表达时引起两种类型的白血病，阻止CrkII蛋白促进细胞迁移。CrkII在C.和哺乳动物。我们测试了C. Abl的elegans同源物ABL-1可抑制吞噬。我们发现ABL-1作为凋亡细胞吞噬和细胞迁移的抑制剂发挥作用。然而，我们的分析进一步表明，ABL-1并不通过抑制其他已知的吞噬蛋白，包括C。秀丽隐杆线虫CrkII.我们的数据表明ABL-1阻断ABI-1，C.哺乳动物和果蝇的β-interactor（Abi）细胞内调节蛋白的同源物。我们认为ABL-1通过ABI-1抑制细胞尸体吞噬和细胞迁移过程中新发现的通路。我们证明了C. elegans Abl（ABL-1）通过一条新定义的途径抑制凋亡细胞的吞噬，该途径包括C.细胞骨架调节因子β-相互作用因子的同源物。
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 includes the adaptor protein CED-2 CrkII and the small GTPase CED-10 Rac, and acts to rearrange the cytoskeleton of the engulfing cell. The other pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Although many components required for engulfment have been identified, little is known about inhibition of engulfment. The tyrosine kinase Abl regulates the actin cytoskeleton in mammals and Drosophila in multiple ways. For example, Abl inhibits cell migration via phosphorylation of CrkII. We tested whether ABL-1, the C. elegans ortholog of Abl, inhibits the CED-2 CrkII-dependent engulfment of apoptotic cells. Our genetic studies indicate that ABL-1 inhibits apoptotic cell engulfment, but not through CED-2 CrkII, and instead acts in parallel to the two known engulfment pathways. 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 loss of ABL-1 function partially restores normal DTC migration in the CED-10 Rac pathway mutants. We found that ABI-1 the C. elegans homolog of mammalian Abi (Abl interactor) proteins, is required for engulfment of apoptotic cells and proper DTC migration. Like Abl, Abi proteins are cytoskeletal regulators. ABI-1 acts in parallel to the two known engulfment pathways, likely downstream of ABL-1. ABL-1 and ABI-1 interact physically in vitro. We propose that ABL-1 opposes the engulfment of apoptotic cells by inhibiting ABI-1 via a pathway that is distinct from the two known engulfment pathways. Cell death or apoptosis is a normal part of animal development, as is the engulfment and removal of dead cells by other cells. In the nematode Caenorhabditis elegans, ten highly conserved proteins have been characterized previously for their roles in engulfment and in cell migration, both of which involve the formation of cellular extensions. Little is known, however, about how engulfment is inhibited. In mammals, the tyrosine kinase Abl, which regulates the actin cytoskeleton and which when misexpressed causes two types of leukemia, prevents the CrkII protein from facilitating cell migration. CrkII functions in engulfment in C. elegans and mammals. We tested whether the C. elegans homolog of Abl, ABL-1, could inhibit engulfment. We found that ABL-1 functions as an inhibitor of apoptotic cell engulfment and cell migration. However, our analysis further showed that ABL-1 does not function by inhibiting other known engulfment proteins, including C. elegans CrkII. Our data indicate that ABL-1 blocks ABI-1, the C. elegans homolog of the mammalian and Drosophila Abl-interactor (Abi) cytoskeletal-regulatory proteins. We propose that ABL-1 acts via ABI-1 to inhibit a newly identified pathway during cell corpse engulfment and cell migration. We show thatC. elegans Abl (ABL-1) inhibits the engulfment of apoptotic cells via a newly defined pathway that includes theC. elegans homolog of the cytoskeletal regulator Abl-interactor.
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