Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia.
Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia.
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DOI：
10.1083/jcb.201609033
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发表时间：
2017-05-01
期刊：
影响因子：
--
通讯作者：
Reid E
中科院分区：
文献类型：
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作者：
Allison R;Edgar JR;Pearson G;Rizo T;Newton T;Günther S;Berner F;Hague J;Connell JW;Winkler J;Lippincott-Schwartz J;Beetz C;Winner B;Reid E
遗传性痉挛性截瘫（HSP）是一种遗传异质性疾病，由许多基因突变引起，包括编码痉挛素，strumpelin或REEP 1的基因。Allison等表明，相似的溶酶体表型与不同类别的HSP蛋白的突变相关，并表明ER-内体接触缺陷和内体小管分裂可能是该疾病中轴突变性的常见原因。内体和内质网（ER）之间的接触促进内体小管分裂，但所涉及的机制和小管分裂失败的后果还不完全清楚。我们发现，微管切断酶痉挛和ESCRT蛋白IST 1在ER-内体接触驱动内体小管分裂之间的相互作用。分裂失败导致甘露糖6-磷酸受体的分选缺陷，从而破坏溶酶体酶运输和异常溶酶体形态，包括小鼠原代神经元和人干细胞衍生的神经元。与ER介导的内体小管分裂在溶酶体功能中的作用一致，在缺乏WASH复合物组分strumpelin或ER形态原REEP 1的细胞模型中观察到类似的溶酶体异常。痉挛素、strumpelin或REEP 1的突变导致遗传性痉挛性截瘫（HSP），这是一种以轴突变性为特征的疾病。我们的研究结果暗示在轴突病的ER-内体接触过程的失败，并表明ER介导的内体小管分裂与溶酶体功能的耦合将以前被认为功能不同的不同类别的HSP蛋白连接到轴突变性的统一途径中。
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disease caused by mutations in many genes, including those encoding spastin, strumpellin, or REEP1. Allison et al. show that similar lysosomal phenotypes are associated with mutations in different classes of HSP proteins and suggest that defective ER–endosome contacts and endosome tubule fission may be a common cause of axon degeneration in the disease. Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER–endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell–derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in spastin, strumpellin, or REEP1 cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER–endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.