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  • 1
    Publication Date: 2019
    Description: 〈sec〉〈st〉Synopsis〈/st〉〈p〉〈textbox textbox-type="graphic"〉〈p〉〈inline-fig〉〈/inline-fig〉〈/p〉〈/textbox〉〈/p〉 〈p〉Phosphoinositides are key regulators of small GTP-binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5K act sequentially to generate PI(4,5)P〈sub〉2〈/sub〉, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKMH1 release from late endosomes.〈/p〉 〈p〉 〈l type="unord"〉〈li〉〈p〉PI4K2A is key for PI4P production in Rab7-positive endosomes.〈/p〉〈/li〉 〈li〉〈p〉PIP5K converts PI4P to PI(4,5)P〈sub〉2〈/sub〉 at late endosomes to inactivate Rab7.〈/p〉〈/li〉 〈li〉〈p〉PI4K2A or PIP5K depletion impairs acidification of autophagosomes.〈/p〉〈/li〉 〈li〉〈p〉The conversion of PI4P to PI(4,5)P〈sub〉2〈/sub〉 promotes the release of PLEKHM1 from late endosome.〈/p〉〈/li〉〈/l〉 〈/p〉〈/sec〉
    Print ISSN: 0261-4189
    Electronic ISSN: 1460-2075
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2019
    Description: 〈p〉The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP-bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7-positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)P〈sub〉2〈/sub〉 causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)P〈sub〉2〈/sub〉 production. Deletion of PI4K2A greatly reduces PIP5K-mediated PI(4,5)P〈sub〉2〈/sub〉 production in Rab7-positive endosomes leading to impaired Rab7 inactivation and increased number of LC3-positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P-PI(4,5)P〈sub〉2〈/sub〉-dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.〈/p〉
    Print ISSN: 0261-4189
    Electronic ISSN: 1460-2075
    Topics: Biology , Medicine
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