N⁶-adenosine methylation enhances nuclear mRNA export through METTL3 and NUP93

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Nuclear export of messenger RNAs (mRNAs) via nuclear pore complexes (NPCs) is essential for gene expression.
• The role of N⁶-adenosine methylation (m⁶A) in mRNA nuclear export remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which m⁶A influences mRNA nuclear export.
• To identify the key proteins involved in m⁶A-mediated mRNA export.

Main Methods:

• Single-molecule imaging to observe mRNA export dynamics.
• Biochemical assays to study protein-protein interactions.
• Analysis of a disease-associated variant in NUP93.

Main Results:

• m⁶A significantly enhances the efficiency and speed of messenger ribonucleoprotein (mRNP) nuclear export.
• The m⁶A methyltransferase METTL3 interacts with NUP93 at NPCs, facilitating m⁶A-modified mRNP export.
• A steroid-resistant nephrotic syndrome (SRNS)-associated NUP93 variant disrupts METTL3 binding, impairing mRNA export and kidney function.

Conclusions:

• A novel regulatory axis involving m⁶A, METTL3, and NUP93 controls nuclear mRNA export.
• Defects in this axis can lead to diseases such as SRNS due to impaired mRNA export.
• This discovery has significant implications for understanding gene expression regulation and human diseases.