O-GlcNAc transferase regulates intervertebral disc degeneration by targeting FAM134B-mediated ER-phagy.

Both O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and endoplasmic reticulum-phagy (ER-phagy) are well-characterized conserved adaptive regulatory mechanisms that maintain cellular homeostasis and function in response to various stress conditions. Abnormalities in O-GlcNAcylation and ER-phagy have been documented in a wide variety of human pathologies. However, whether O-GlcNAcylation or ER-phagy is involved in the pathogenesis of intervertebral disc degeneration (IDD) is largely unknown. In this study, we investigated the function of O-GlcNAcylation and ER-phagy and the related underlying mechanisms in IDD. We found that the expression profiles of O-GlcNAcylation and O-GlcNAc transferase (OGT) were notably increased in degenerated NP tissues and nutrient-deprived nucleus pulposus (NP) cells. By modulating the O-GlcNAc level through genetic manipulation and specific pharmacological intervention, we revealed that increasing O-GlcNAcylation abundance substantially enhanced cell function and facilitated cell survival under nutrient deprivation (ND) conditions. Moreover, FAM134B-mediated ER-phagy activation was regulated by O-GlcNAcylation, and suppression of ER-phagy by FAM134B knockdown considerably counteracted the protective effects of amplified O-GlcNAcylation. Mechanistically, FAM134B was determined to be a potential target of OGT, and O-GlcNAcylation of FAM134B notably reduced FAM134B ubiquitination-mediated degradation. Correspondingly, the protection conferred by modulating O-GlcNAcylation homeostasis was verified in a rat IDD model. Our data demonstrated that OGT directly associates with and stabilizes FAM134B and subsequently enhances FAM134B-mediated ER-phagy to enhance the adaptive capability of cells in response to nutrient deficiency. These findings may provide a new option for O-GlcNAcylation-based therapeutics in IDD prevention.