UBC9‐mediated SUMOylation of Lamin B1 enhances DNA‐damage‐induced nuclear DNA leakage and autophagy after spinal cord injury

• Published in: Journal of cellular physiology Vol. 239; no. 5; pp. e31213 - n/a
• Main Authors: Fan, Yun‐peng, Lou, Jun‐sheng, Jin, Meng‐ran, Zhou, Cong‐hui, Shen, Hong‐hao, Fu, Chun‐yan, Mao, Xing‐jia, Chen, Ying‐ying, Zhong, Jin‐jie, Wang, Lin‐lin, Wu, Jun‐song
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2024
• Subjects: Accumulation; Animals; Autophagy; Cell Nucleus - metabolism; Cells, Cultured; Damage; Deoxyribonucleic acid; DNA; DNA Damage; Immunofluorescence; Immunoprecipitation; Injury analysis; Lamin B1; Lamin Type B - genetics; Lamin Type B - metabolism; Leakage; Mice; Neurons; Neurons - metabolism; Neurons - pathology; nucleophagy; Proteins; Rats; Rats, Sprague-Dawley; siRNA; Spinal cord injuries; Spinal Cord Injuries - genetics; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - pathology; SUMO protein; SUMOylation; Transfection; UBC9; Ubiquitin; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Lamin B1; SUMOylation; UBC9; nucleophagy; DNA damage
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.31213

Recent studies have shown that nucleophagy can mitigate DNA damage by selectively degrading nuclear components protruding from the nucleus. However, little is known about the role of nucleophagy in neurons after spinal cord injury (SCI). Western blot analysis and immunofluorescence were performed to evaluate the nucleophagy after nuclear DNA damage and leakage in SCI neurons in vivo and NSC34 expression in primary neurons cultured with oxygen–glucose deprivation (OGD) in vitro, as well as the interaction and colocalization of autophagy protein LC3 with nuclear lamina protein Lamin B1. The effect of UBC9, a Small ubiquitin‐related modifier (SUMO) E2 ligase, on Lamin B1 SUMOylation and nucleophagy was examined by siRNA transfection or 2‐D08 (a small‐molecule inhibitor of UBC9), immunoprecipitation, and immunofluorescence. In SCI and OGD injured NSC34 or primary cultured neurons, neuronal nuclear DNA damage induced the SUMOylation of Lamin B1, which was required by the nuclear Lamina accumulation of UBC9. Furthermore, LC3/Atg8, an autophagy‐related protein, directly bound to SUMOylated Lamin B1, and delivered Lamin B1 to the lysosome. Knockdown or suppression of UBC9 with siRNA or 2‐D08 inhibited SUMOylation of Lamin B1 and subsequent nucleophagy and protected against neuronal death. Upon neuronal DNA damage and leakage after SCI, SUMOylation of Lamin B1 is induced by nuclear Lamina accumulation of UBC9. Furthermore, it promotes LC3‐Lamin B1 interaction to trigger nucleophagy that protects against neuronal DNA damage. Upon neuronal DNA damage and leakage after spinal cord injury,, SUMOylation of Lamin B1 is induced by nuclear lamina accumulation of UBC9. Furthermore, it promotes LC3‐Lamin B1 interaction to trigger nucleophagy that protects against neuronal DNA damage.