The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways.

Andrea Gubas,David G Mcewan,Marina E Hoffmann,Anna Platzek,Nina Dawe,Doris Popovic,Christina Karantanou,Georg Tascher,Ivan Dikic,Daniela S Krause

doi:10.1002/1873-3468.14041

Abstract

The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain-containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 coprecipitates with, and is directly phosphorylated by, mTOR. Using a phosphospecific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2-mediated phosphorylation in a growth factor-dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor- and amino acid-sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

Highlights

FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
We identified Pleckstrin homology domain-containing family member 1 (PLEKHM1) as an interaction partner of Rab7 [25] and subsequently showed that PLEKHM1 is present on LAMP1/LAMP2/ Rab7-positive vesicles, which facilitates the fusion of autophagosomes and lysosomes [26] and influences the Salmonella-containing vacuole (SCV) formation [25]
Since we found mTOR complex 2 (mTORC2) components coprecipitating with PLEKHM1 (Fig. 1A,B), we cannot rule out a role for mTORC2-mediated PLEKHM1 phosphorylation at S432/S435

Summary

Introduction

Pleckstrin homology domain-containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. Using a phosphospecific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2-mediated phosphorylation in a growth factor-dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor- and amino acid-sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

Methods

Results

Conclusion