Beclin 1 Phosphorylation - at the Center of Autophagy Regulation

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.

Keywords: ATG; BECN1; PI3K; autophagy; beclin; kinase; phosphorylation.

FIGURE 1

Autophagy and Beclin 1 (BECN1) phosphorylation. (A) The scheme depicts the phases of autophagosome assembly from initiation to nutrient recycling. The steps include the structural transformation from the pre-autophagosomal structure (PAS) to phagophore to autophagosomes, culminating in the fusion of autophagosomes with lysosomes facilitating the degradation of their contents in autolysosomes. The regulatory protein complexes involved are depicted with their components and the presence of regulatory phosphorylation event/events are shown. (B) Primary structure of BECN1 showing the BCL2/BCL-XL binding BH3 motif (residues 105–130), flexible helical domain (F, residues 141–171), and the central coiled coil domain (CCD, residues 175–265). Evolutionary conserved domain (residues 248–337) and β/α-repeated, autophagy-related (BARA) domain (265–450aa) is represented together as ECD-BARA (Mei et al., 2016). The approximate locations of pro-autophagy (green) and inhibitory (red) phosphorylation sites are shown. The contributions of the different domains to complex formation with interactors are also indicated. (C) Phosphorylation-dependent conversion of inactive BECN1 homodimer/BCL2-complex to an active PI3K-III complex is depicted. The STK4-mediated BECN1-BH3 domain phosphorylation (negative regulator of autophagy), triple phosphorylation of BCL2 which releases BCL2 from BECN1, representative phosphorylation events in the N-terminal domain (NTD) promoting BECN1-BCL2 dissociation as well as activating the PI3K-activity are presented (positive regulation).