Emerging roles of O-GlcNAcylation in protein trafficking and secretion

Abstract

The emerging roles of O-GlcNAcylation, a distinctive post-translational modification, are increasingly recognized for their involvement in the intricate processes of protein trafficking and secretion. This modification exerts its influence on both conventional and unconventional secretory pathways. Under healthy and stress conditions, such as during diseases, it orchestrates the transport of proteins within cells, ensuring timely delivery to their intended destinations. O-GlcNAcylation occurs on key factors, like coat protein complexes (COPI and COPII), clathrin, SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors), and GRASP55 (Golgi reassembly stacking protein of 55 kDa) that control vesicle budding and fusion in anterograde and retrograde trafficking and unconventional secretion. The understanding of O-GlcNAcylation offers valuable insights into its critical functions in cellular physiology and the progression of diseases, including neurodegeneration, cancer, and metabolic disorders. In this review, we summarize and discuss the latest findings elucidating the involvement of O-GlcNAc in protein trafficking and its significance in various human disorders.

Keywords: COPI; COPII; GRASP55; O-GlcNAcylation; autophagy; cancer; clathrin; conventional secretion; exosome; metabolic disease; neurodegeneration; protein trafficking; unconventional secretion.

Figure 1

O-GlcNAcylation regulates ER–Golgi trafficking in the conventional secretory pathway. Three components of the COPII coat (Sec31, Sec23, and Sec24) are modified with O-GlcNAc, and this modification affects COPII vesicle budding at the ER exit site (ERES) and ER-to-Golgi trafficking. The COPγ1 subunit of the COPI coat is also O-GlcNAcylated, but its role in Golgi-to-ER trafficking requires further investigation. COPI, coat protein complex I; COPII, coat protein complex II; ER, endoplasmic reticulum.

Figure 2

De-O-GlcNAcylation of GRASP55 and SNAP-29 facilitates autophagosome–lysosome fusion under starvation. Under growth condition, the Golgi stacking protein GRASP55, but not its homolog GRASP65, is O-GlcNAcylated. Upon starvation, GRASP55 becomes de-O-GlcNAcylated and relocates from the Golgi to autophagosome–lysosome interface, where the de-O-GlcNAcylated form of GRASP55 acts as a membrane tether, facilitating autophagosome–lysosome fusion by bridging LC3 and LAMP2. In addition, SNAP-29 also undergoes dynamic O-GlcNAcylation, and when de-GlcNAcylated, it promotes the formation of SNARE complexes, thereby facilitating the fusion of autophagosomes with lysosomes. Whether there is any communication between GRASP55 and SNAP-29 under stressful conditions remains an intriguing and unanswered question. GRASP55, Golgi reassembly stacking protein of 55 kDa.

Figure 3

O-GlcNAcylation modulates exosome secretion. In this illustration, we depict the dual role of O-GlcNAcylation in modulating exosome secretion. On one hand, de-O-GlcNAcylated SNAP-23 accelerates exosome release through the formation of the VAMP8–SNAP-23–STX-4 SNARE complex, influencing the process at a global level. Conversely, O-GlcNAcylation of cargo proteins, including αB-crystallin and hnRNPA2B1, facilitates their exosome secretion. The precise mechanisms by which O-GlcNAcylation governs exosome secretion in different cellular contexts or scenarios warrant further investigation to elucidate the seemingly contrasting effects.