PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression.
PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression.
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DOI：
10.1038/s41467-022-32543-2
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发表时间：
2022-08-15
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
常染色体显性遗传性多囊肾病(ADPKD)是人类最常见的遗传病之一，也是肾衰竭的常见病因之一，主要由PKD1杂合子突变引起。当PKD1的剂量低于临界阈值时，就会发生肾囊肿形成。然而，没有框架存在来控制剩余的等位基因或逆转PKD1的下降。在这里，我们证明了由未失活的PKD1等位基因产生的mRNAs是通过它们的3‘-UTRmiR-17结合元件被抑制的。消除这个基序(PKD1mRNA17)可以提高∆的稳定性，提高多囊蛋白-1的水平，并减缓细胞、体外和小鼠PKD模型中的囊泡生长。值得注意的是，PKD2还通过其3‘-UTRmiR-17基序被抑制，并且PKD2∆17诱导的多囊蛋白-2去抑制在PKD1突变模型中延缓了包囊的生长。此外，急性阻断PKD1/2顺式抑制，包括在囊性发作后，可减弱小鼠的PKD。最后，在患者来源的原代ADPKD培养中对PKD1Creb17或PKD2ADPKD17等位基因进行建模可以使囊泡更小，减少增殖，降低pCreb1的表达，并改善线粒体膜电位。因此，避免3‘-UTR顺式干扰和增强PKD/2mRNA的翻译是一种潜在的突变不可知的ADPKD抑制方法。ADPKD是一种常见的肾衰竭病因，由PKD1或PKD2杂合突变引起。在这里，作者表明，阻止由未灭活的PKD1/2等位基因产生的3‘-UTR顺式抑制mRNAs可以改善临床前的ADPKD。
Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation occurs when PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are repressed via their 3′-UTR miR-17 binding element. Eliminating this motif (Pkd1∆17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also inhibited via its 3′-UTR miR-17 motif, and Pkd2∆17-induced Polycystin-2 derepression retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, modeling PKD1∆17 or PKD2∆17 alleles in patient-derived primary ADPKD cultures leads to smaller cysts, reduced proliferation, lower pCreb1 expression, and improved mitochondrial membrane potential. Thus, evading 3′-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach. ADPKD, a common aetiology of kidney failure, is caused by heterozygous PKD1 or PKD2 mutations. Here the authors show that preventing 3′-UTR cis-inhibition of mRNAs produced by the non-inactivated PKD1/2 alleles ameliorates preclinical ADPKD.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
19.6
作者：
Kleczko EK;Marsh KH;Tyler LC;Furgeson SB;Bullock BL;Altmann CJ;Miyazaki M;Gitomer BY;Harris PC;Weiser-Evans MCM;Chonchol MB;Clambey ET;Nemenoff RA;Hopp K
通讯作者：
Hopp K
影响因子：
16
作者：
Eisen, Timothy J.;Eichhorn, Stephen W.;Bartel, David P.
通讯作者：
Bartel, David P.
DOI：
10.2215/cjn.02320220
发表时间：
2021-05-08
影响因子：
9.8
作者：
Lanktree, Matthew B.;Haghighi, Amirreza;Pei, York
通讯作者：
Pei, York
影响因子：
15.9
作者：
Hopp, Katharina;Ward, Christopher J.;Harris, Peter C.
通讯作者：
Harris, Peter C.