Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion
| Autor: | Tamas Balla, Yeun Ju Kim, Nivedita Sengupta, Daniel J Toth, Takashi Baba |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Phosphatidylinositol 4
5-Diphosphate Autophagosome Endosome Autophagy-Related Proteins Endosomes Biology Membrane Fusion General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound VPS35 0302 clinical medicine Lysosome medicine Humans Small GTPase Molecular Biology Adaptor Proteins Signal Transducing 030304 developmental biology 0303 health sciences Membrane Glycoproteins General Immunology and Microbiology General Neuroscience Autophagy Autophagosomes rab7 GTP-Binding Proteins Articles Endocytosis PI4K2A Cell biology Protein Transport HEK293 Cells medicine.anatomical_structure Phosphatidylinositol 4 5-bisphosphate chemistry rab GTP-Binding Proteins Lysosomes Corrigendum 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | The EMBO Journal. 38 |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.15252/embj.2018100312 |
| Popis: | 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(2) 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(2) production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)P(2) 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(2)‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. |
| Databáze: | OpenAIRE |
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