The Lysosomal Storage Disorder Due to fig4a Mutation Causes Robust Liver Vacuolation in Zebrafish
The Lysosomal Storage Disorder Due to fig4a Mutation Causes Robust Liver Vacuolation in Zebrafish
复制标题
Fig4a突变导致的溶酶体贮积症导致斑马鱼肝脏出现强烈空泡
DOI：
10.1089/zeb.2020.1911
复制
发表时间：
2021-04-26
期刊：
影响因子：
2
通讯作者：
Ni, Rui
中科院分区：
文献类型：
--
作者：
Bao, Wandong;Wang, Xinjuan;Ni, Rui
磷脂磷酸酶FIG 4/Fig 4是PIKFYVE/Pikfyve激酶复合物的亚基，其合成磷脂酰肌醇3，5-二磷酸（PI（3，5）P-2），磷脂酰肌醇3，5-二磷酸（PI（3，5）P-2）是内溶酶体运输和功能的关键调节剂。FIG 4/Fig 4的缺失导致PI（3，5）P-2信号传导的细胞内缺陷和多种内溶酶体缺陷。先前的工作集中在人类临床和动物研究中FIG 4/Fig 4突变在神经和肌肉骨骼系统中的作用。在这项研究中，我们描述了一个斑马鱼隐性突变体cq 35显示出强大的肝空泡化和致死性，预测截断突变fig 4a基因。在恢复正常的fig 4a转录后，fig 4a突变体的肝空泡化过程是可逆的。肝空泡化病理被确定为异常溶酶体储存，具有大量累积的货物，包括自噬中间体，并导致突变肝脏中胆小管的进行性变性。fig 4a突变体的这些肝脏病理学细节在斑马鱼pikfyve突变体中重复。因此，斑马鱼具有Pikfyve激酶复合物中保守的结构和功能机制，基于此，Pikfyve突变体表型在其双突变体中覆盖了fig 4a突变体表型。我们的研究结果代表了第一次描述的体内缺陷所造成的FIG 4/Fig 4突变或PI（3，5）P-2缺陷在肝脏中，并揭示了保守的复杂机制与FIG 4/Fig 4缺陷的疾病在斑马鱼。
The phospholipid phosphatase FIG4/Fig4 is a subunit of PIKFYVE/Pikfyve kinase complex that synthesizes phosphatidylinositol 3,5-bisphosphate (PI(3,5)P-2), a key regulator of endolysosomal trafficking and function. Loss of FIG4/Fig4 leads to intracellular deficiency of PI(3,5)P-2 signaling and multiple endolysosomal defects. Previous works were focused on the effects of FIG4/Fig4 mutations in the nervous and musculoskeletal systems in human clinical and animal studies. In this study, we describe a zebrafish recessive mutant cq35 showing robust liver vacuolation and lethality, with a predicted truncating mutation in fig4a gene. The liver vacuolation progress in fig4a mutant was reversible after regaining normal fig4a transcripts. The hepatic vacuolation pathology was identified as abnormal lysosomal storage with numerous accumulated cargoes, including autophagy intermediates, and caused progressive degeneration of bile canaliculi in mutant liver. These hepatic pathological details of fig4a mutant were repeated in zebrafish pikfyve mutant. Thus, zebrafish possess the conserved structural and functional mechanisms in Pikfyve kinase complex, based on which, pikfyve mutant phenotype covered fig4a mutant phenotype in their double mutant. Our findings represent the first description of the in vivo defects caused by FIG4/Fig4 mutation or PI(3,5)P-2 deficiency in liver, and reveal the conserved complex mechanisms associated with FIG4/Fig4-deficient disorders in zebrafish.