Finding the Missing Link Between the Unfolded Protein Response and O-GlcNAcylation in the Heart
X-box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway Wang et al Cell. 2014;156:1179–1192.
The endoplasmic reticulum (ER) stress–inducible transcription factor, x-box binding protein 1 (XBP1), which enhances protein glycosylation in the ER, was shown to also enhance protein glycosylation outside the ER, via a process called O-GlcNAcylation, which protected the heart from ischemia/reperfusion damage.
O-GlcNAcylation is a reversible post-translational modification that takes place outside of the ER and affects the functions of target proteins. In cardiac myocytes, O-GlcNAcylation increases acutely in response to a variety of conditions, including hypoxia, ischemia, ischemia/reperfusion, and oxidative stress, during which O-GlcNAcylation is generally protective. However, chronic increases in O-GlcNAcylation during diseases, such as diabetes mellitus, exacerbate cardiac dysfunction and damage. In contrast to O-GlcNAcylation, N-linked glycosylation (N-glycosylation) of proteins occurs in the ER, is relatively permanent, and is required for folding and trafficking of proteins in the ER and Golgi. N-glycosylation can be impaired by many of the same stresses that affect O-GlcNAcylation in the heart. Impaired N-glycosylation causes ER stress, subsequent activation of the unfolded protein response (UPR), and activation of the transcription factor, XBP1, which induces genes that restore N-glycosylation in the ER and promote adaptation to ER stress. A recent study, published in the journal Cell, showed that XBP1 also enhances O-GlcNAcylation, which protects the heart from ischemia/reperfusion damage.1 Thus, in response to potentially damaging stress, XBP1 coordinates glycosylation inside and outside of the ER to confer protection.
The study by Wang et al1 showed that XBP1 is the missing link between protein O-GlcNAcylation and the UPR (Figure [A]). In the heart, ischemia/reperfusion leads to ER stress, activation of the UPR and XBP1, which Wang et al determined to be a direct transcriptional activator of the gene encoding the rate-limiting step in the hexosamine biosynthetic pathway, which supplies the substrate required for O-GlcNAcylation, that is, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). These …