Regulation of the hypertonic stress response by the 3' mRNA cleavage and polyadenylation complex.
Regulation of the hypertonic stress response by the 3' mRNA cleavage and polyadenylation complex.
复制标题
通过 3 mRNA 裂解和聚腺苷酸化复合物调节高渗应激反应。
DOI：
10.1093/genetics/iyad051
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发表时间：
2023
期刊：
影响因子：
3.3
通讯作者：
Lamitina,Todd
中科院分区：
文献类型：
--
作者：
Urso,SarelJ;Sathaseevan,Anson;BrentDerry,W;Lamitina,Todd
渗透压稳态的维持是生理学中最积极防御的稳态设定点之一。渗透稳态的一个主要机制涉及蛋白质的上调，该蛋白质催化称为有机渗压剂的溶质的积累。为了更好地了解渗透压物质积累蛋白是如何调节的，我们在秀丽隐杆线虫中进行了正向遗传筛选，以寻找不诱导渗透压物质生物合成基因表达的突变体（Nio突变体）。突变体3编码错义突变incpf-2/CstF 64，而突变体7编码错义突变symk-1/Symplekin。cpf-2和symk-1是高度保守的3′ mRNA切割和多聚腺苷酸化复合物的核组分，cpf-2和symk-1阻断了gpdh-1和其他诱导性mRNA的高渗诱导，表明它们在转录水平起作用。我们为symk-1克隆了一个生长素诱导的降解决定子（AID）等位基因，并发现在肠和皮下组织中的急性发育后降解足以导致Nio表型。symk-1和cpf-2表现出遗传相互作用，强烈表明它们通过改变3′ mRNA切割和/或选择性多聚腺苷酸化发挥功能。与此假设一致，我们发现抑制mRNA切割复合物的其他几种组分也会导致Nio表型。cpf-2和symk-1特异性地影响渗透胁迫反应，因为热休克诱导的ahsp-16.2：：GFP报告基因的上调在这些突变体中是正常的。我们的数据表明，在一个模型中，交替聚腺苷酸化的1个或多个mRNA是必不可少的调节高渗应激反应。
Maintenance of osmotic homeostasis is one of the most aggressively defended homeostatic set points in physiology. One major mechanism of osmotic homeostasis involves the upregulation of proteins that catalyze the accumulation of solutes called organic osmolytes. To better understand how osmolyte accumulation proteins are regulated, we conducted a forward genetic screen inCaenorhabditis elegansfor mutants with no induction of osmolyte biosynthesis gene expression (Nio mutants). Thenio-3mutant encoded a missense mutation incpf-2/CstF64, while thenio-7mutant encoded a missense mutation insymk-1/Symplekin. Bothcpf-2andsymk-1are nuclear components of the highly conserved 3′ mRNA cleavage and polyadenylation complex.cpf-2andsymk-1block the hypertonic induction ofgpdh-1and other osmotically induced mRNAs, suggesting they act at the transcriptional level. We generated a functional auxin-inducible degron (AID) allele forsymk-1and found that acute, post-developmental degradation in the intestine and hypodermis was sufficient to cause the Nio phenotype.symk-1andcpf-2exhibit genetic interactions that strongly suggest they function through alterations in 3′ mRNA cleavage and/or alternative polyadenylation. Consistent with this hypothesis, we find that inhibition of several other components of the mRNA cleavage complex also cause a Nio phenotype.cpf-2andsymk-1specifically affect the osmotic stress response since heat shock-induced upregulation of ahsp-16.2::GFPreporter is normal in these mutants. Our data suggest a model in which alternative polyadenylation of 1 or more mRNAs is essential to regulate the hypertonic stress response.