The accumulation of unfolded proteins in the endoplasmic reticulum (ER), a condition known as ER stress, induces a cellular response called the unfolded protein response (UPR). Although ER stress and the UPR have been shown to affect glucose metabolism in neurons by activating enzymes that promote glycogen formation, this connection is less studied in other cell types. Now, Petros Petrou and colleagues (Lytridou et al., 2020) investigate the effects of ER stress on glycogen metabolism in myoblasts. They find that activation of ER stress in myoblasts results in the formation of glycogen clusters and induces the expression of the glycogen-binding protein Stbd1. Stbd1 knockdown and mutation of its glycogen-binding domain impair glycogen clustering, suggesting that Stbd1 is essential for the formation of glycogen clusters in response to ER stress. The authors also show that inhibition of PERK, a mediator of the UPR, interferes with ER stress-induced Stbd1 upregulation and glycogen clustering, indicating that UPR activation by PERK induces Stbd1 expression and glycogen clustering. Interestingly, the absence of glycogen clusters in Stbd1 knockdown cells also correlates with an increased susceptibility to apoptosis, indicating that the presence of glycogen clusters may support cell survival upon ER stress. Collectively, these findings identify Stbd1 as a critical factor in regulating glycogen metabolism in response to ER stress in myoblasts, which may support ER homeostasis or cellular metabolism to promote cell survival.
