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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