Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
Division of Biological Sciences, University of California, San Diego, California, USA.
Dev Dyn. 2020 Aug;249(8):1018-1031. doi: 10.1002/dvdy.173. Epub 2020 Apr 14.
The self-assembly of metabolic enzymes into filaments or foci highlights an intriguing mechanism for the regulation of metabolic activity. Recently, we identified the conserved polymerization of phosphoribosyl pyrophosphate synthetase (PRPS), which catalyzes the first step in purine nucleotide synthesis, in yeast and cultured mammalian cells. While previous work has revealed that loss of PRPS activity regulates retinal development in zebrafish, the extent to which PRPS filament formation affects tissue development remains unknown.
By generating novel alleles in the zebrafish PRPS paralogs, prps1a and prps1b, we gained new insight into the role of PRPS filaments during eye development. We found that mutations in prps1a alone are sufficient to generate abnormally small eyes along with defects in head size, pigmentation, and swim bladder inflation. Furthermore, a loss-of-function mutation that truncates the Prps1a protein resulted in the failure of PRPS filament assembly. Lastly, in mutants that fail to assemble PRPS filaments, we observed disorganization of the actin network in the lens fibers.
The truncation of Prps1a blocked PRPS filament formation and resulted in a disorganized lens fiber actin network. Altogether, these findings highlight a potential role for PRPS filaments during lens fiber organization in zebrafish.
代谢酶自组装成丝或焦点突出了代谢活性调节的一种有趣机制。最近，我们在酵母和培养的哺乳动物细胞中鉴定了磷酸核糖焦磷酸合成酶（PRPS）的保守聚合，该酶催化嘌呤核苷酸合成的第一步。虽然以前的工作表明 PRPS 活性的丧失调节斑马鱼的视网膜发育，但 PRPS 丝形成对组织发育的影响程度尚不清楚。
通过在斑马鱼 PRPS 旁系同源物 prps1a 和 prps1b 中生成新的等位基因，我们深入了解了 PRPS 丝在眼睛发育过程中的作用。我们发现，仅 prps1a 的突变足以产生眼睛异常小，以及头部大小，色素沉着和鳔膨胀的缺陷。此外，截断 Prps1a 蛋白的功能丧失突变导致 PRPS 丝组装失败。最后，在无法组装 PRPS 丝的突变体中，我们观察到晶状体纤维中的肌动蛋白网络紊乱。
Prps1a 的截断阻止了 PRPS 丝的形成，并导致晶状体纤维肌动蛋白网络紊乱。总之，这些发现强调了 PRPS 丝在斑马鱼晶状体纤维组织中的潜在作用。
