Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction.
Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction.
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DOI：
10.1016/j.jbc.2023.105158
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发表时间：
2023-09
影响因子：
4.8
通讯作者：
Weimbs, Thomas
中科院分区：
文献类型：
--
作者：
Pellegrini, Hannah;Sharpe, Elizabeth H.;Liu, Guangyi;Nishiuchi, Eiko;Doerr, Nicholas;Kipp, Kevin R.;Chin, Tiffany;Schimmel, Margaret F.;Weimbs, Thomas
编码多囊蛋白-1（PC 1）的基因突变是常染色体显性多囊肾病（ADPKD）的最常见原因。ADPKD囊肿表现为Warburg样代谢，其特征为线粒体功能障碍和有氧糖酵解。PC 1是一种完整的膜蛋白，具有大的胞外结构域和短的C-末端胞质尾，与G蛋白偶联受体具有结构和功能相似性。其确切功能尚不清楚。PC 1的C-末端胞质尾区发生蛋白水解切割，产生在ADPKD肾脏中过表达的可溶性片段。这些片段的调节、定位和功能知之甚少。在这里，我们表明，一个30 kDa的裂解片段（PC 1-p30），包括整个C-末端的尾巴，经历了快速的蛋白酶体降解的机制，涉及冯希佩尔-林道肿瘤抑制蛋白。PC 1-p30受活性氧稳定，亚细胞定位受活性氧剂量依赖性调节。我们发现，第二个，约15 kDa的片段（PC 1-p15），产生的半胱天冬酶切割在一个保守的网站（Asp-4195）的PC 1 C-末端尾巴。PC 1-p15不受降解，组成性定位于线粒体基质。这两个裂解片段诱导线粒体片段化，PC 1-p15表达导致脂肪酸氧化受损和乳酸产生增加，表明Warburg样表型。内源性PC 1尾片段在PKD小鼠模型中的肾囊衬里细胞中积累。总的来说，这些结果确定了新的机制，关于PC 1的调节和功能，并表明，C-末端PC 1片段可能涉及在ADPKD中观察到的线粒体和代谢异常。
Mutations in the gene encoding polycystin-1 (PC1) are the most common cause of autosomal dominant polycystic kidney disease (ADPKD). Cysts in ADPKD exhibit a Warburg-like metabolism characterized by dysfunctional mitochondria and aerobic glycolysis. PC1 is an integral membrane protein with a large extracellular domain, a short C-terminal cytoplasmic tail and shares structural and functional similarities with G protein–coupled receptors. Its exact function remains unclear. The C-terminal cytoplasmic tail of PC1 undergoes proteolytic cleavage, generating soluble fragments that are overexpressed in ADPKD kidneys. The regulation, localization, and function of these fragments is poorly understood. Here, we show that a ∼30 kDa cleavage fragment (PC1-p30), comprising the entire C-terminal tail, undergoes rapid proteasomal degradation by a mechanism involving the von Hippel-Lindau tumor suppressor protein. PC1-p30 is stabilized by reactive oxygen species, and the subcellular localization is regulated by reactive oxygen species in a dose-dependent manner. We found that a second, ∼15 kDa fragment (PC1-p15), is generated by caspase cleavage at a conserved site (Asp-4195) on the PC1 C-terminal tail. PC1-p15 is not subject to degradation and constitutively localizes to the mitochondrial matrix. Both cleavage fragments induce mitochondrial fragmentation, and PC1-p15 expression causes impaired fatty acid oxidation and increased lactate production, indicative of a Warburg-like phenotype. Endogenous PC1 tail fragments accumulate in renal cyst-lining cells in a mouse model of PKD. Collectively, these results identify novel mechanisms regarding the regulation and function of PC1 and suggest that C-terminal PC1 fragments may be involved in the mitochondrial and metabolic abnormalities observed in ADPKD.
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影响因子：
3.4
作者：
Liu D;Liu Y;Xia Z;Dong H;Yi Z
通讯作者：
Yi Z
影响因子：
15.9
作者：
Chauvet, V;Tian, X;Caplan, MJ
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影响因子：
81.5
作者：
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DOI：
10.1152/ajprenal.00348.2010
发表时间：
2011-05-01
影响因子：
4.2
作者：
Belibi, Franck;Zafar, Iram;Edelstein, Charles L.
通讯作者：
Edelstein, Charles L.
影响因子：
4.3
作者：
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