Beclin 1 Phosphorylation - at the Center of Autophagy Regulation.

Manoj B Menon,Sonam Dhamija

doi:10.3389/fcell.2018.00137

Abstract

Autophagy is a tightly regulated catabolic process wherein cells under stress sequester cytosolic constituents like damaged proteins and organelles in double-membrane vesicles called autophagosomes. The autophagosomes degrade their cargo by lysosomal proteolysis generating raw materials for the biosynthesis of vital macromolecules. One of the initial steps in the assembly of autophagosomes from pre-autophagic structures is the recruitment and activation of the class III phosphatidylinositol 3-kinase complex consisting of Beclin 1 (BECN1), VPS34, VPS15, and ATG14 proteins. Several pieces of evidence indicate that the phosphorylation and ubiquitination of BECN1 at an array of residues fine-tune the responses to diverse autophagy modulating stimuli and helps in maintaining the balance between pro-survival autophagy and pro-apoptotic responses. In this mini-review, we will discuss the importance of distinct BECN1 phosphorylation events, the diverse signaling pathways and kinases involved and their role in the regulation of autophagy.

Highlights

Macro-autophagy, usually referred to as “autophagy” is a catabolic process by which cells subject cytosolic components for lysosomal degradation and recycling, often in response to metabolic stress or nutrient starvation (Bento et al, 2016)
In response to the metabolic needs of the cells, autophagy is initiated by the concerted action of the ATG1/ULK1 (Unc-51 like autophagy activating kinase-1) complex and the PI3K-III complex
This leads to the nucleation of phagophores which engulf intracellular cargo generating double-membranous structures called autophagosomes, which eventually fuse with lysosomes to form autolysosomes wherein the contents are degraded to release amino acids and other metabolites (Figure 1A; Bento et al, 2016)

Summary

INTRODUCTION

Macro-autophagy, usually referred to as “autophagy” is a catabolic process by which cells subject cytosolic components for lysosomal degradation and recycling, often in response to metabolic stress or nutrient starvation (Bento et al, 2016). In response to the metabolic needs of the cells, autophagy is initiated by the concerted action of the ATG1 (autophagy related 1)/ULK1 (Unc-51 like autophagy activating kinase-1) complex and the PI3K-III complex. This leads to the nucleation of phagophores which engulf intracellular cargo generating double-membranous structures called autophagosomes, which eventually fuse with lysosomes to form autolysosomes wherein the contents are degraded to release amino acids and other metabolites (Figure 1A; Bento et al, 2016). Being the master nutrient sensor, the mTORC1 (mammalian target of rapamycin complex 1) signaling is the primary regulator of autophagy initiation in mammalian cells (Kim and Guan, 2015; Rabanal-Ruiz et al, 2017). Loss of mTORC1 activity during amino-acid and nutrient starvation releases this break on ULK1

Beclin Phosphorylation in Autophagy

Findings

Effect on autophagy