Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 345 Weill Hall, Ithaca, NY, 14853, USA.
Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Mol Neurodegener. 2017 Aug 23;12(1):62. doi: 10.1186/s13024-017-0205-9.
Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. PGRN is localized to the lysosome and important for proper lysosome function. However, the metabolism of PGRN in the lysosome is still unclear.
Here, we report that PGRN is processed into ~10 kDa peptides intracellularly in multiple cell types and tissues and this processing is dependent on lysosomal activities. PGRN endocytosed from the extracellular space is also processed in a similar manner. We further demonstrated that multiple cathepsins are involved in PGRN processing and cathepsin L cleaves PGRN in vitro.
Our data support that PGRN is processed in the lysosome through the actions of cathepsins.
导致颗粒体蛋白前体（PGRN）单倍不足的突变会引起 TDP-43 阳性包涵体的额颞叶变性（FTLD-TDP），这是一种破坏性的神经退行性疾病。PGRN 定位于溶酶体，对溶酶体的正常功能很重要。然而，溶酶体中 PGRN 的代谢仍不清楚。
在这里，我们报告说，PGRN 在多种细胞类型和组织中被细胞内加工成约 10 kDa 的肽，并且这种加工依赖于溶酶体的活性。从细胞外空间内吞的 PGRN 也以类似的方式被加工。我们进一步证明，多种组织蛋白酶参与 PGRN 的加工，组织蛋白酶 L 在体外切割 PGRN。
我们的数据支持 PGRN 通过组织蛋白酶在溶酶体中被加工。
