CUP-5, the C. elegans ortholog of the mammalian lysosomal channel protein MLN1/TRPML1, is required for proteolytic degradation in autolysosomes
CUP-5, the C. elegans ortholog of the mammalian lysosomal channel protein MLN1/TRPML1, is required for proteolytic degradation in autolysosomes
复制标题
DOI：
10.4161/auto.7.11.17759
复制
发表时间：
2011-11
期刊：
影响因子：
13.3
通讯作者：
Tao Sun;Xingwei Wang;Q. Lu;Haiyan Ren;Hong Zhang
中科院分区：
文献类型：
--
作者：
Tao Sun;Xingwei Wang;Q. Lu;Haiyan Ren;Hong Zhang
巨自噬（本文称为自噬）的过程涉及封闭双膜结构（称为自噬体）的形成，以及随后与溶酶体融合形成自噬溶酶体。隔离材料降解后，溶酶体由自溶酶体再生。在这项研究中，我们发现编码线虫 Mucolipin 1 同源物的 cup-5 的突变会导致自噬途径缺陷。在 cup-5 突变体中，多种自噬底物积聚在扩大的液泡中，显示出晚期内体和溶酶体的特征，表明自噬溶酶体中的蛋白水解降解有缺陷。我们进一步发现，在自噬活性丧失的突变体中，体腔细胞（位于体腔中的清道夫细胞）中的溶酶体尺寸更小，数量更多。此外，cup-5突变体扩大的液泡积累异常和胚胎致死率因自噬活性降低而部分受到抑制。我们的结果表明，自噬活性的基础组成水平调节溶酶体的大小和数量，并为了解粘脂沉积症 IV 型疾病的分子机制提供了见解。
The process of macroautophagy (herein referred to as autophagy) involves the formation of a closed double-membrane structure, called the autophagosome, and its subsequent fusion with lysosomes to form an autolysosome. Lysosomes are regenerated from autolysosomes after degradation of the sequestrated materials. In this study, we showed that mutations in cup-5, encoding the C. elegans Mucolipin 1 homolog, cause defects in the autophagy pathway. In cup-5 mutants, a variety of autophagy substrates accumulate in enlarged vacuoles that display characteristics of late endosomes and lysosomes, indicating defective proteolytic degradation in autolysosomes. We further revealed that lysosomes in coelomocytes (scavenger cells located in the body cavity) are smaller in size and more numerous in mutants with loss of autophagy activity. Furthermore, the enlarged vacuole accumulation abnormality and embryonic lethality of cup-5 mutants are partially suppressed by reduced autophagy activity. Our results indicate that the basal constitutive level of autophagy activity regulates the size and number of lysosomes and provides insights into the molecular mechanisms underlying mucolipidosis type IV disease.