Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Mol Biol Cell. 2010 Jul 15;21(14):2434-42. doi: 10.1091/mbc.e09-12-1010. Epub 2010 May 19.
Late endocytic organelles including lysosomes are highly dynamic acidic organelles. Late endosomes and lysosomes directly fuse for content mixing to form hybrid organelles, from which lysosomes are reformed. It is not fully understood how these processes are regulated and maintained. Here we show that the Caenorhabditis elegans ARL-8 GTPase is localized primarily to lysosomes and involved in late endosome-lysosome fusion in the macrophage-like coelomocytes. Loss of arl-8 results in an increase in the number of late endosomal/lysosomal compartments, which are smaller than wild type. In arl-8 mutants, late endosomal compartments containing endocytosed macromolecules fail to fuse with lysosomal compartments enriched in the aspartic protease ASP-1. Furthermore, loss of arl-8 strongly suppresses formation of enlarged late endosome-lysosome hybrid organelles caused by mutations of cup-5, which is the orthologue of human mucolipin-1. These findings suggest that ARL-8 mediates delivery of endocytosed macromolecules to lysosomes by facilitating late endosome-lysosome fusion.
晚期内吞细胞器包括溶酶体是高度动态的酸性细胞器。晚期内体和溶酶体直接融合进行内容混合，形成混合细胞器，然后从该混合细胞器中再重新形成溶酶体。目前尚不完全清楚这些过程是如何被调控和维持的。在这里，我们发现秀丽隐杆线虫的 ARL-8 GTP 酶主要定位于溶酶体，并参与巨噬细胞样体腔细胞中的晚期内体-溶酶体融合。arl-8 的缺失导致晚期内体/溶酶体隔室的数量增加，这些隔室比野生型小。在 arl-8 突变体中，包含内吞大分子的晚期内体隔室未能与富含天冬氨酸蛋白酶 ASP-1 的溶酶体隔室融合。此外，arl-8 的缺失强烈抑制了由 cup-5 突变引起的大的晚期内体-溶酶体混合细胞器的形成，cup-5 是人类粘脂素-1 的同源物。这些发现表明，ARL-8 通过促进晚期内体-溶酶体融合，介导内吞大分子向溶酶体的运输。
