A caspase-RhoGEF axis contributes to the cell size threshold for apoptotic death in developing Caenorhabditis elegans.
A caspase-RhoGEF axis contributes to the cell size threshold for apoptotic death in developing Caenorhabditis elegans.
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DOI：
10.1371/journal.pbio.3001786
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发表时间：
2022-10
期刊：
影响因子：
9.8
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中科院分区：
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细胞的大小会影响其死亡的可能性。但在这种情况下，细胞大小是如何控制的，细胞大小如何影响对细胞死亡命运的承诺？我们提出的证据表明，caspase CED-3在秀丽隐杆线虫神经母细胞中与Rhogef ECT-2相互作用，产生“不需要的”细胞。我们认为，这种相互作用促进了极肌动球蛋白的收缩，从而导致神经母细胞分裂不平等，并产生了低于临界“致命”大小阈值的子细胞。此外，我们发现ECT-2 Rhogef的过度激活减少了不需要的细胞的大小。重要的是，这抑制了由Ced-3半胱氨酸氨基转移酶部分缺失引起的“细胞死亡异常”表型，从而增加了不想要的细胞死亡的可能性。然而，Ced-3 caspase的一个假定的零突变不被抑制，这表明细胞大小影响CED-3 caspase的激活和/或活性。因此，我们发现了细胞凋亡途径和细胞大小之间的新的顺序和相互作用，影响细胞对细胞死亡命运的承诺。本研究表明，在线虫神经母细胞的发育过程中，caspase CED-3与Rhogef ECT-2相互作用，导致肌动球蛋白的变化和这些细胞的不平等分裂。这揭示了半胱氨酸天冬氨酸酶的一种非规范功能，在这种功能中，半胱氨酸天冬氨酸氨基转移酶有助于确保注定要进行凋亡的子代细胞的大小低于一个关键的“致命”阈值。
A cell’s size affects the likelihood that it will die. But how is cell size controlled in this context and how does cell size impact commitment to the cell death fate? We present evidence that the caspase CED-3 interacts with the RhoGEF ECT-2 in Caenorhabditis elegans neuroblasts that generate “unwanted” cells. We propose that this interaction promotes polar actomyosin contractility, which leads to unequal neuroblast division and the generation of a daughter cell that is below the critical “lethal” size threshold. Furthermore, we find that hyperactivation of ECT-2 RhoGEF reduces the sizes of unwanted cells. Importantly, this suppresses the “cell death abnormal” phenotype caused by the partial loss of ced-3 caspase and therefore increases the likelihood that unwanted cells die. A putative null mutation of ced-3 caspase, however, is not suppressed, which indicates that cell size affects CED-3 caspase activation and/or activity. Therefore, we have uncovered novel sequential and reciprocal interactions between the apoptosis pathway and cell size that impact a cell’s commitment to the cell death fate. This study shows that in developing C. elegans neuroblasts, the caspase CED-3 interacts with the RhoGEF ECT-2, leading to changes in actomyosin and the unequal division of these cells. This reveals a non-canonical function of caspases, wherein they help establish ensure that the size of daughter cells fated for apoptosis is below a critical ’lethal’ threshold.