Phosphatidylinositol 4,5-bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome-lysosome fusion

The EMBO Journal
Takashi BabaTamas Balla

Abstract

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)P2 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)P2 production. Deletion of PI4K2A greatly reduces PIP5Kγ-mediated PI(4,5)P2 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)P2 -dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.

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Citations

Nov 7, 2019·The FEBS Journal·Lavinia PalamiucBrooke M Emerling
Jun 6, 2020·Journal of Cell Science·Lena DehnenAchim Paululat
Aug 7, 2019·Biochemical Society Transactions·Michael EbnerVolker Haucke
Dec 7, 2019·Traffic·Mariana E G de AraujoLukas A Huber
Oct 30, 2020·The Journal of Clinical Investigation·Meagan J McGrathChristina A Mitchell
Oct 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Cynthia López-HaberAdriana R Mantegazza
Jun 19, 2021·Frontiers in Cell and Developmental Biology·Hongyuan JinHangyu Li
Jul 1, 2021·Journal of Bioenergetics and Biomembranes·Carrie HiserShelagh Ferguson-Miller
Jan 18, 2020·Langmuir : the ACS Journal of Surfaces and Colloids·Jonas SchäferClaudia Steinem

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Autophagosome

An autophagosome is the formation of double-membrane vesicles that involve numerous proteins and cytoplasmic components. These double-membrane vesicles are then terminated at the lysosome where they are degraded. Discover the latest research on autophagosomes here.

Autophagosome

An autophagosome is the formation of double-membrane vesicles that involve numerous proteins and cytoplasmic components. These double-membrane vesicles are then terminated at the lysosome where they are degraded. Discover the latest research on autophagosomes here.