Actin remodeling mediates ROS production and JNK activation to drive apoptosis-induced proliferation.
Actin remodeling mediates ROS production and JNK activation to drive apoptosis-induced proliferation.
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DOI：
10.1371/journal.pgen.1010533
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发表时间：
2022-12
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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应激诱导的细胞死亡，主要是凋亡，及其随后的组织修复是相互联系的，尽管我们对这种联系的认识仍然非常有限。一个有趣的发现是凋亡诱导的增殖（AiP），凋亡细胞触发其相邻细胞的补偿性增殖的进化保守机制。使用果蝇作为模式生物的研究已经揭示了凋亡半胱天冬酶和c-Jun N-末端激酶（JNK）信号传导在激活AiP中起关键作用。例如，引发剂胱天蛋白酶Dronc（果蝇中的胱天蛋白酶-9直系同源物）促进JNK的活化，导致促有丝分裂信号和AiP的释放。最近的研究进一步揭示，Dronc通过Myo 1D（一种非常规肌球蛋白）重新定位到细胞皮层，并刺激活性氧（ROS）的产生以触发AiP。在这个过程中，ROS可以吸引血细胞，果蝇巨噬细胞，这进一步非自主地扩增JNK信号细胞。然而，在应激信号产生细胞内连接Dronc、ROS和JNK的内在组分仍然难以捉摸。在这里，我们确定了LIM结构域激酶1（LIMK 1），一种促进细胞F-肌动蛋白聚合的激酶，作为一种新的AiP调节剂。F-actin以Dronc依赖的方式积累，以响应凋亡应激。通过敲低LIMK 1或表达Cofilin（一种F-肌动蛋白延伸的抑制剂）来抑制应激细胞中的F-肌动蛋白聚合，从而阻断ROS产生和JNK活化，因此产生AiP。此外，Dronc和LIMK 1在基因上相互作用。Dronc和LIMK 1的共表达驱动F-肌动蛋白积累、ROS产生和JNK活化。有趣的是，Dronc和LIMK 1之间的这些协同效应取决于Myo 1D。因此，F-actin重构在AiP过程中介导caspase驱动的ROS产生和JNK激活起重要作用。在多细胞生物体中，受损细胞通常通过细胞凋亡（程序性细胞死亡的主要形式）去除。有趣的是，这些凋亡细胞可以发出信号，以诱导其邻近细胞的增殖，以维持组织的稳态，这种现象称为凋亡诱导的增殖（AiP）。半胱天冬酶是一个众所周知的执行细胞凋亡的半胱氨酸蛋白酶家族，也通过激活JNK（一种应激反应激酶）在触发AiP中起关键作用。在这项研究中，我们确定了肌动蛋白细胞骨架，一个动态的结构网络的细胞，作为一个关键的介导JNK激活AiP。在此过程中，肌动蛋白丝经历增加的聚合，这取决于LIM结构域激酶1（LIMK 1）。在遗传学上，半胱天冬酶和LIMK 1共同促进肌动蛋白聚合，从而驱动活性氧（ROS）的产生和随后的JNK激活。因此，我们的研究发现了肌动蛋白重塑在垂死细胞中的作用，其介导半胱天冬酶在AiP和组织修复中的非凋亡作用。
Stress-induced cell death, mainly apoptosis, and its subsequent tissue repair is interlinked although our knowledge of this connection is still very limited. An intriguing finding is apoptosis-induced proliferation (AiP), an evolutionary conserved mechanism employed by apoptotic cells to trigger compensatory proliferation of their neighboring cells. Studies using Drosophila as a model organism have revealed that apoptotic caspases and c-Jun N-terminal kinase (JNK) signaling play critical roles to activate AiP. For example, the initiator caspase Dronc, the caspase-9 ortholog in Drosophila, promotes activation of JNK leading to release of mitogenic signals and AiP. Recent studies further revealed that Dronc relocates to the cell cortex via Myo1D, an unconventional myosin, and stimulates production of reactive oxygen species (ROS) to trigger AiP. During this process, ROS can attract hemocytes, the Drosophila macrophages, which further amplify JNK signaling cell non-autonomously. However, the intrinsic components connecting Dronc, ROS and JNK within the stressed signal-producing cells remain elusive. Here, we identified LIM domain kinase 1 (LIMK1), a kinase promoting cellular F-actin polymerization, as a novel regulator of AiP. F-actin accumulates in a Dronc-dependent manner in response to apoptotic stress. Suppression of F-actin polymerization in stressed cells by knocking down LIMK1 or expressing Cofilin, an inhibitor of F-actin elongation, blocks ROS production and JNK activation, hence AiP. Furthermore, Dronc and LIMK1 genetically interact. Co-expression of Dronc and LIMK1 drives F-actin accumulation, ROS production and JNK activation. Interestingly, these synergistic effects between Dronc and LIMK1 depend on Myo1D. Therefore, F-actin remodeling plays an important role mediating caspase-driven ROS production and JNK activation in the process of AiP. In multicellular organisms, damaged cells are frequently removed via apoptosis, the major form of programmed cell death. Intriguingly, these apoptotic cells can emit signals to induce proliferation of their neighboring cells for the maintenance of tissue homeostasis, a phenomenon termed apoptosis-induced proliferation (AiP). Caspases, a family of cysteine proteases well known to execute apoptosis, also play a critical role to trigger AiP via activation of JNK, a stress response kinase. In this study, we identified the actin cytoskeleton, a dynamic structural network of the cell, as a key mediator of JNK activation in AiP. During this process, actin filaments undergo increased polymerization which depends on LIM domain kinase 1 (LIMK1). Genetically, caspases and LIMK1 work together to promote actin polymerization, which in turn drives production of reactive oxygen species (ROS) and the subsequent activation of JNK. Therefore, our study discovered a role of actin remodeling in dying cells which mediates the non-apoptotic roles of caspases in AiP and tissue repair.
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DOI：
10.1146/annurev-cellbio-032320-094706
发表时间：
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影响因子：
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Kadzik RS;Homa KE;Kovar DR
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