ABSTRACT

WDR45 and WDR45B are β-propeller proteins belonging to the WIPI (WD repeat domain, phosphoinositide interacting) family. Mutations in WDR45 and WDR45B are genetically linked with beta-propeller protein-associated neurodegeneration (BPAN) and intellectual disability (ID), respectively. WDR45 and WDR45B are homologs of yeast Atg18. Atg18 forms a complex with Atg2 for autophagosome biogenesis, probably by transferring lipids from the ER to phagophores. We revealed that WDR45 and WDR45B are critical for autophagosome-lysosome fusion in neural cells. WDR45 and WDR45B, but not their disease-related mutants, bind to the tether protein EPG5 and facilitate its targeting to late endosomes/lysosomes. In Wdr45 Wdr45b-deficient cells, the formation of tether-SNARE fusion machinery is compromised. The macroautophagy/autophagy deficiency in wdr45 wdr45b DKO cells is ameliorated by suppression of O-GlcNAcylation, which promotes autophagosome maturation. Thus, our results provide insights into the pathogenesis of WDR45- and WDR45B-related neurological diseases.

摘要

WDR45 和 WDR45B 是属于 WIPI（WD 重复结构域，磷酸肌醇相互作用）家族的 β-螺旋桨蛋白。WDR45和WDR45B的突变在基因上分别与 β-螺旋桨蛋白相关神经变性 (BPAN) 和智力障碍 (ID) 相关。WDR45 和 WDR45B 是酵母 Atg18 的同源物。Atg18 与 Atg2 形成复合物用于自噬体的生物发生，可能是通过将脂质从 ER 转移到吞噬细胞。我们发现 WDR45 和 WDR45B 对神经细胞中的自噬体-溶酶体融合至关重要。WDR45 和 WDR45B，但不是它们的疾病相关突变体，与系链蛋白 EPG5 结合并促进其靶向晚期内体/溶酶体。在Wdr45 Wdr45b-缺陷细胞，系绳-SNARE 融合机制的形成受到损害。wdr45 wdr45b DKO 细胞中的巨自噬/自噬缺陷通过抑制O -GlcNAcylation 得到改善，O-GlcNAcylation 促进自噬体成熟。因此，我们的结果提供了对WDR45和WDR45B相关神经系统疾病发病机制的见解。