Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.
Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.
复制标题
DOI：
10.1038/s41467-023-42196-4
复制
发表时间：
2023-10-16
影响因子：
16.6
通讯作者：
Qian, Feng
中科院分区：
文献类型：
--
作者：
Walker, Rebecca, V;Yao, Qin;Xu, Hangxue;Maranto, Anthony;Swaney, Kristen F.;Ramachandran, Sreekumar;Li, Rong;Cassina, Laura;Polster, Brian M.;Outeda, Patricia;Boletta, Alessandra;Watnick, Terry;Qian, Feng
由PKHD 1编码的纤维囊蛋白/多导管蛋白（FPC）与常染色体隐性遗传性多囊肾病（ARPKD）相关，但其在囊肿发生中的确切作用仍不清楚。在这里，我们表明，FPC经历复杂的蛋白水解过程中发展的肾脏，产生三个可溶性C-末端片段（ICD）。值得注意的是，ICD 15在其N-末端含有新的线粒体靶向序列，促进其易位到线粒体中。这增强了肾上皮细胞中的线粒体呼吸，部分恢复了由FPC损失引起的线粒体功能受损。FPC失活导致肾小管线粒体超微结构形态异常，无囊肿形成。此外，FPC失活显著加剧了肾脏囊肿形成，并在Pkd 1小鼠突变体Pkd 1V/V中触发了严重的胰腺囊肿形成，其中Pkd 1编码的多囊蛋白-1在GPCR蛋白水解位点的裂解被阻断。在Pkd 1V/V小鼠中，删除ICD 15可增强肾囊肿形成而不诱导胰腺囊肿。这些发现揭示了FPC和线粒体途径之间通过ICD 15切割的直接联系，这对囊肿发生机制至关重要。Fibrocystin/Polyductin（FPC）是由PKHD 1编码的大的睫状膜蛋白，当突变时，其导致ARPKD。在这里，作者表明FPC通过其C末端产物的释放和线粒体易位抑制小鼠模型肾脏中的囊肿发育。
Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms. Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by PKHD1 which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.
登录
查看更多内容
影响因子：
10.5
作者：
Harris PC;Torres VE
通讯作者：
Torres VE
影响因子：
0.4
作者：
Guay-Woodford LM
通讯作者：
Guay-Woodford LM
影响因子：
6.1
作者：
Ahrabi, Ali K.;Jouret, Francois;Devuyst, Olivier
通讯作者：
Devuyst, Olivier
影响因子：
4.8
作者：
Hiesberger, Thomas;Gourley, Eric;Igarashi, Peter
通讯作者：
Igarashi, Peter
影响因子：
30.8
作者：
通讯作者：
--