OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates.
OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates.
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DOI：
10.1091/mbc.e15-06-0329
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发表时间：
2016-01-01
影响因子：
3.3
通讯作者：
Lowe M
中科院分区：
文献类型：
--
作者：
Billcliff PG;Noakes CJ;Mehta ZB;Yan G;Mak L;Woscholski R;Lowe M
Lowe综合征蛋白OCRL 1通过IPIP 27 A与F-BAR蛋白pacsin 2结合，以促进在trans-Golgi网络和内体处含有甘露糖6-磷酸受体的运输中间体的生物合成。肌醇5-磷酸酶OCRL 1的突变导致Lowe综合征和Dent-2病。OCRL 1功能的丧失扰乱了几个细胞过程，包括膜交通，但其潜在机制仍然不清楚。在这里，我们表明，OCRL 1的膜贩运机器的一部分，在trans-Golgi网络（TGN）/内体接口操作。OCRL 1通过IPIP 27 A与F-BAR蛋白pacsin 2相互作用。OCRL 1和IPIP 27 A定位于含有甘露糖6-磷酸受体（MPR）的运输中间体，并且任一蛋白质的缺失导致TGN和内体处有缺陷的MPR载体生物合成。OCRL 1 5-磷酸酶活性是膜曲率敏感性的，通过IPIP 27 A介导的OCRL 1与pacsin 2的接合刺激，并促进含MPR载体的断裂。我们的数据表明OCRL 1通过IPIP 27 A在调节pacsin 2依赖性运输中间体的形成中发挥作用，并揭示了PtdIns（4，5）P2水解与内膜上载体生物发生偶联的机制。
The Lowe syndrome protein OCRL1 binds via IPIP27A to the F-BAR protein pacsin 2 to promote the biogenesis of trafficking intermediates containing the mannose 6-phosphate receptor at the trans-Golgi network and endosomes. Mutation of the inositol 5-phosphatase OCRL1 causes Lowe syndrome and Dent-2 disease. Loss of OCRL1 function perturbs several cellular processes, including membrane traffic, but the underlying mechanisms remain poorly defined. Here we show that OCRL1 is part of the membrane-trafficking machinery operating at the trans-Golgi network (TGN)/endosome interface. OCRL1 interacts via IPIP27A with the F-BAR protein pacsin 2. OCRL1 and IPIP27A localize to mannose 6-phosphate receptor (MPR)–containing trafficking intermediates, and loss of either protein leads to defective MPR carrier biogenesis at the TGN and endosomes. OCRL1 5-phosphatase activity, which is membrane curvature sensitive, is stimulated by IPIP27A-mediated engagement of OCRL1 with pacsin 2 and promotes scission of MPR-containing carriers. Our data indicate a role for OCRL1, via IPIP27A, in regulating the formation of pacsin 2–dependent trafficking intermediates and reveal a mechanism for coupling PtdIns(4,5)P2 hydrolysis with carrier biogenesis on endomembranes.