Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis.
Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis.
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DOI：
10.7554/elife.67828
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发表时间：
2021-07-12
期刊：
影响因子：
7.7
通讯作者：
Scott JD
中科院分区：
文献类型：
--
作者：
Gopalan J;Omar MH;Roy A;Cruz NM;Falcone J;Jones KN;Forbush KA;Himmelfarb J;Freedman BS;Scott JD
水稳态的病理生理缺陷可导致肾衰竭。同样地，与肾集合管中异常细胞骨架动力学和睫状体隔室中干扰的钙和cAMP信号传导相关的常见遗传性疾病促成慢性肾衰竭。我们发现缺乏A-激酶锚定蛋白AKAP 220的小鼠集合管表现出增强的初级纤毛发育。机制研究表明，AKAP 220相关的蛋白磷酸酶1（PP 1）介导这种表型，促进组蛋白脱乙酰基酶6（HDAC 6）的稳定性的变化，伴随着肌动蛋白动力学的缺陷。这通过先前未识别的PP 1衔接子功能进行，因为所有纤毛发生和细胞骨架表型在表达磷酸酶靶向缺陷型AKAP 220-Δ PP 1突变体的mIMCD 3敲入细胞中重现。局部HDAC 6活性的药理学阻断改变了纤毛发育，并减少了肾芯片和类器官模型中的囊肿形成。这些发现将AKAP 220-PPI-HDAC 6途径确定为初级纤毛发育中的关键效应子。
Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.
影响因子：
3.7
作者：
Parnell SC;Puri S;Wallace DP;Calvet JP
通讯作者：
Calvet JP