Cell Biology and Physiology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 50 South Drive, Building 50, Room 3537, Bethesda, MD, 20892, USA.
Department of Cell Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Room S332 Biomedical Sciences Tower, Pittsburgh, PA, 15213, USA.
Nat Commun. 2017 Nov 17;8(1):1580. doi: 10.1038/s41467-017-01871-z.
Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end. TMEM55B overexpression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery. TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress. TMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome-lysosome fusion. Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions.
溶酶体的分布与其在许多细胞功能中的作用有关，包括自噬体降解、胆固醇稳态、抗原呈递和细胞侵袭。溶酶体定位的改变导致了不同的人类疾病，如癌症、神经退行性疾病和溶酶体贮积症。在这里，我们报告了一种新的溶酶体运输调节机制。我们发现，溶酶体跨膜蛋白 TMEM55B 将 JIP4 募集到溶酶体表面，诱导溶酶体沿着微管的负端向动力蛋白依赖的运输。TMEM55B 的过表达导致溶酶体塌陷到细胞中心，而 TMEM55B 或 JIP4 的耗尽则导致溶酶体向细胞外周分散。在饥饿或胆固醇诱导的溶酶体应激下，TFEB 和 TFE3 的激活会导致 TMEM55B 的转录上调。TMEM55B 或 JIP4 的耗竭会阻止饥饿诱导的溶酶体逆行运输，并阻止自噬体-溶酶体融合。总的来说，我们的数据表明，TFEB/TMEM55B/JIP4 途径协调溶酶体在各种应激条件下的运动。
