Antagonistic control of lysosomal fusion by Rab14 and the Lyst-related protein LvsB.
Antagonistic control of lysosomal fusion by Rab14 and the Lyst-related protein LvsB.
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DOI：
10.1111/tra.12058
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
De Lozanne A
中科院分区：
文献类型：
--
作者：
Kypri E;Falkenstein K;De Lozanne A
虽然缺乏Lyst蛋白会导致Chediak-Higashi综合征患者溶酶体异常，但Lyst对溶酶体生物学的贡献尚不清楚。先前我们发现Lyst的盘基骨柱同源物LvsB是一种细胞质蛋白，它与溶酶体和后溶酶体结合以防止它们的不适当融合。在这里，我们提供了三条证据，表明LvsB通过拮抗DdRab14的功能来促进溶酶体的功能，DdRab14是一种促进溶酶体之间同型融合的蛋白质。(1)缺乏LvsB的细胞并没有将DdRab14局限于溶酶体，而是将DdRab14的定位扩展到溶酶体后。(2)活化的DdRab14的表达表现了LvsB的缺失，导致溶酶体和后溶酶体之间不适当的异型融合以及随后的扩增。(3)相反，表达失活的DdRab14可抑制LvsB细胞的表型，恢复其溶酶体大小和与后溶酶体的分离。我们的数据表明LvsB与晚期溶酶体结合并促进DdRab14失活的情况。这种失活使溶酶体成熟为后溶酶体以供最终分泌。我们认为，人Lyst可能具有类似的功能，以调节rab依赖性溶酶体区室的融合。
While loss of the protein Lyst causes abnormal lysosomes in patients with Chediak-Higashi Syndrome, the contribution of Lyst to lysosome biology is not known. Previously we found that the Dictyostelium ortholog of Lyst, LvsB, is a cytosolic protein that associates with lysosomes and post-lysosomes to prevent their inappropriate fusion. Here we provide three lines of evidence that indicate that LvsB contributes to lysosome function by antagonizing the function of DdRab14, a protein that promotes homotypic fusion among lysosomes. (1) Instead of restricting DdRab14 to lysosomes, cells that lack LvsB expand DdRab14 localization to include post-lysosomes. (2) Expression of activated DdRab14 phenocopies the loss of LvsB, causing inappropriate heterotypic fusion between lysosomes and post-lysosomes and their subsequent enlargement. (3) Conversely, expression of inactivated DdRab14 suppresses the phenotype of LvsB null cells and restores their lysosomal size and segregation from post-lysosomes. Our data suggest a scenario where LvsB binds to late lysosomes and promotes the inactivation of DdRab14. This inactivation allows the lysosomes to mature into post-lysosomes for eventual secretion. We propose that human Lyst may function similarly to regulate Rab-dependent fusion of lysosomal compartments.
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