Osnabrück University, Department of Biology/Chemistry, Biochemistry section, Barbarastrasse 13, 49076 Osnabrück, Germany.
Department of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center Groningen, 9700 Groningen, The Netherlands.
J Cell Sci. 2022 Apr 15;135(8). doi: 10.1242/jcs.259421. Epub 2022 Apr 28.
Lysosomes mediate degradation of macromolecules to their precursors for cellular recycling. Additionally, lysosome-related organelles mediate cell type-specific functions. Chédiak-Higashi syndrome is an autosomal, recessive disease, in which loss of the protein LYST causes defects in lysosomes and lysosome-related organelles. The molecular function of LYST, however, is largely unknown. Here, we dissected the function of the yeast LYST homolog, Bph1. We show that Bph1 is an endosomal protein and an effector of the minor Rab5 isoform Ypt52. Strikingly, bph1Δ mutant cells have lipidated Atg8 on their endosomes, which is sorted via late endosomes into the vacuole lumen under non-autophagy-inducing conditions. In agreement with this, proteomic analysis of bph1Δ vacuoles reveals an accumulation of Atg8, reduced flux via selective autophagy, and defective endocytosis. Additionally, bph1Δ cells have reduced autophagic flux under starvation conditions. Our observations suggest that Bph1 is a novel Rab5 effector that maintains endosomal functioning. When Bph1 is lost, Atg8 is lipidated at endosomes even during normal growth and ends up in the vacuole lumen. Thus, our results contribute to the understanding of the role of LYST-related proteins and associated diseases.
溶酶体介导大分子降解为其细胞回收的前体。此外，溶酶体相关细胞器介导细胞类型特异性功能。Chédiak-Higashi 综合征是一种常染色体隐性疾病，其蛋白 LYST 的缺失导致溶酶体和溶酶体相关细胞器缺陷。然而，LYST 的分子功能在很大程度上是未知的。在这里，我们剖析了酵母 LYST 同源物 Bph1 的功能。我们表明 Bph1 是一种内体蛋白，是次要 Rab5 同工型 Ypt52 的效应物。引人注目的是，bph1Δ 突变细胞在内体上具有脂化的 Atg8，在非自噬诱导条件下，通过晚期内体将其分拣到液泡腔中。与此一致的是，bph1Δ 液泡的蛋白质组学分析显示 Atg8 积累，通过选择性自噬的通量减少，以及内吞作用缺陷。此外，bph1Δ 细胞在饥饿条件下自噬通量降低。我们的观察表明，Bph1 是一种维持内体功能的新型 Rab5 效应物。当 Bph1 缺失时，即使在正常生长期间，Atg8 也在内体上被脂化，并最终进入液泡腔。因此，我们的结果有助于理解 LYST 相关蛋白的作用及其相关疾病。
