ALG-2/AGO-Dependent mir-35 Family Regulates DNA Damage-Induced Apoptosis Through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis elegans
ALG-2/AGO-Dependent mir-35 Family Regulates DNA Damage-Induced Apoptosis Through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis elegans
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DOI：
10.1534/genetics.119.302458
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发表时间：
2019-09-01
期刊：
影响因子：
3.3
通讯作者：
Schumacher, Bjoern
中科院分区：
文献类型：
--
作者：
Doll, Markus Alexander;Soltanmohammadi, Najmeh;Schumacher, Bjoern
microRNA（miRNAs）与argonaute（AGO）蛋白相关，以转录后方式调节参与各种细胞过程的基因的表达。在此，我们表明，秀丽隐杆线虫AGO基因的损失导致快速和显着增加的生殖细胞凋亡，在电离辐射（IR）造成的DNA损伤。我们证明突变动物的异常凋亡表型可以通过miRNA家族成员的表达减少来解释。我们发现，IR处理或家族突变体中细胞凋亡水平的增加依赖于C。ERK 1/2 MAPK直系同源物在垂死的生殖细胞中的表达。出乎意料的是，磷酸化发生在caspase激活的下游，并且至少部分地依赖于功能性细胞尸体吞噬机制。因此，我们提出了一个完善的机制，其中的核心凋亡机制的初始促凋亡刺激启动吞噬过程，这反过来又激活MAPK信号转导，以促进基因组受损的生殖细胞的死亡。
MicroRNAs (miRNAs) associate with argonaute (AGO) proteins to post-transcriptionally modulate the expression of genes involved in various cellular processes. Herein, we show that loss of the Caenorhabditis elegans AGO gene results in rapid and significantly increased germ cell apoptosis in response to DNA damage inflicted by ionizing radiation (IR). We demonstrate that the abnormal apoptosis phenotype in mutant animals can be explained by reduced expression of miRNA family members. We show that the increased apoptosis levels in IR-treated or family mutants depend on a transient hyperactivation of the C. elegans ERK1/2 MAPK ortholog in dying germ cells. Unexpectedly, phosphorylation occurs downstream of caspase activation and depends at least in part on a functional cell corpse-engulfment machinery. Therefore, we propose a refined mechanism, in which an initial proapoptotic stimulus by the core apoptotic machinery initiates the engulfment process, which in turn activates MAPK signaling to facilitate the demise of genomically compromised germ cells.