USP1/UAF1-Stabilized METTL3 Promotes Reactive Astrogliosis and Improves Functional Recovery after Spinal Cord Injury through m6A Modification of YAP1 mRNA

Spinal cord injury (SCI) is a devastating trauma of the CNS involving motor and sensory impairment. This study uncovers how a specific protein, METTL3, plays a crucial role in the healing process after SCI. METTL3, stabilized by the USP1/UAF1 complex, promotes a type of healing response called 'reactive astrogliosis,' which is essential for recovery. The researchers found that METTL3 affects the stability of another molecule, YAP1, through a process called m6A modification. This modification helps maintain the stability of YAP1, which is important for the reactive astrogliosis process. By increasing the stability of YAP1 mRNA in an IGF2BP2-dependent manner, METTL3 encourages astrocyte activity. The study suggests that by targeting METTL3, we might be able to develop new treatments for SCI. This approach could help improve the body's natural healing responses, leading to better outcomes for patients with spinal cord injuries. Specifically, they show how the methyltransferase activity of METTL3 plays an essential role in reactive astrogliosis and motor repair.

• 1
  METTL3 is upregulated in reactive astrocytes after SCI and stabilized by the USP1/UAF1 complex, which removes K48-linked ubiquitination of METTL3.
• 2
  Astrocytic METTL3 knockout suppressed reactive astrogliosis after SCI, resulting in increased inflammation, neuronal loss, and impaired functional recovery.
• 3
  METTL3 methylates the 39-UTR region of YAP1 mRNA, maintaining its stability in an IGF2BP2-dependent manner and promoting reactive astrogliosis.