Contreras V, Richardson M A, Hao E, Keiper B D
Department of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Cell Death Differ. 2008 Aug;15(8):1232-42. doi: 10.1038/cdd.2008.46. Epub 2008 May 2.
During mammalian programmed cell death, cleavage of the translation initiation factor 4G proteins (eIF4GI and eIF4GII) by caspase-3 induces the cap-independent synthesis of pro-apoptotic proteins. Apoptosis occurs naturally in the gonad to remove germ cells that are not selected to grow as oocytes and mature into eggs. Here, we describe two major isoforms of Caenorhabditis elegans eIF4G that are derived from a single gene (ifg-1) and their separate roles in germline homeostasis. Full length IFG-1 protein (170 kDa isoform) differs from the shorter isoform (130 kDa) by the inclusion of the N-terminal domain containing the putative eIF4E-binding site required for mRNA cap recognition. Depletion of the cap-associated p170 isoform induced CED-4 expression in oocytes and markedly increased germline apoptotic events, but did not prevent early mitotic germ cell proliferation. Loss of both p170 and p130 suppressed germ cell proliferation and arrested larval development. Evidence suggests that eIF4G isoforms are differentially utilized during oogenesis to regulate germ cell apoptosis. We propose that an alternative mechanism to eIF4G cleavage may be employed in germ cells by changing the availability of the p170 isoform.
在哺乳动物程序性细胞死亡过程中，半胱天冬酶-3对翻译起始因子4G蛋白（eIF4GI和eIF4GII）的切割诱导了促凋亡蛋白的不依赖帽状结构的合成。凋亡在性腺中自然发生，以清除未被选择发育为卵母细胞并成熟为卵子的生殖细胞。在此，我们描述了秀丽隐杆线虫eIF4G的两种主要亚型，它们源自单个基因（ifg-1），以及它们在生殖系稳态中的不同作用。全长IFG-1蛋白（170 kDa亚型）与较短的亚型（130 kDa）的不同之处在于包含N端结构域，该结构域含有mRNA帽识别所需的假定eIF4E结合位点。帽相关的p170亚型的缺失诱导了卵母细胞中CED-4的表达，并显著增加了生殖系凋亡事件，但并未阻止早期有丝分裂生殖细胞的增殖。p170和p130的缺失均抑制了生殖细胞的增殖并使幼虫发育停滞。有证据表明，在卵子发生过程中，eIF4G亚型被不同地利用来调节生殖细胞凋亡。我们提出，通过改变p170亚型的可用性，可以在生殖细胞中采用一种不同于eIF4G切割的替代机制。
