Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy

Abstract

Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a "bulk" degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, "glycophagy" is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major noncanonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including the liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multidisciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux. We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models, and clinical glycogen disease states.

Keywords: Atg8; Gabarapl1; Stbd1; autophagy; glycogen; glycophagy; lysosome.

Figure 1

Schematic of the proposed glycophagy process. Using UDP-glucose as a substrate, the glucose chains in glycogen granules are elongated by glycogen synthase (GS) and branched by glycogen-branching enzyme (GBE). Glycophagy involves the tagging of glycogen with the adapter protein STBD1, which recruits glycogen into the autophagosome by binding to GABARAPL1. The mature glycophagosome fuses with a lysosome where GAA degrades glycogen to free glucose for metabolic recycling. BRUCE, baculovirus IAP repeat-containing ubiquitin-conjugating enzyme; GAA, acid α-glucosidase.

Figure 2

STBD1 protein domains, interacting proteins, posttranslational modifications, and putative subcellular locations. The glycogen-binding protein, STBD1 (orange), contains two putative functional Atg8-interacting motifs (AIMs) potentially regulated by phosphorylation of serine (S) residues located N-terminally to the AIM site. The carbohydrate-binding domain (CBM20) binds to glycogen. Evidence suggests that Gabarapl1 is the Atg8 family protein that binds to AIM1. AMP-activated protein kinase (AMPK) has been shown to phosphorylate Ser175 and may be involved in regulating the AIM1–Gabarapl1 interaction. Several glycogen-related proteins bind to the CBM20 site including laforin, glycogen-debranching enzyme, and glycogen synthase. Myristoylation (Myr) of the N terminus may play a role in determining subcellular location, and the endoplasmic reticulum (ER) and/or the golgi apparatus may be the site of STBD1 localization and phagophore nucleation.