METTL1 interacts with XPO5 to modulate pre-miRNA export

Area of Science:

• Molecular Biology
• Epigenetics
• RNA Biology

Background:

• The methyltransferase-like 1 (METTL1) protein is known for its role in m7G methylation.
• However, its protein interactions and broader functions are not well understood.

Purpose of the Study:

• To identify proteins interacting with METTL1.
• To elucidate METTL1's role in miRNA biogenesis and export.

Main Methods:

• APEX2-mediated proximity labeling followed by LC-MS/MS analysis.
• Co-immunoprecipitation and western blot assays.
• Genetic manipulation (METTL1 ablation) and ERK activation studies.

Main Results:

• Identified 60 unique proteins interacting with METTL1, including exportin-5 (XPO5).
• METTL1 deficiency caused XPO5 to move to the cytosol, accelerating pre-miRNA export and miRNA maturation.
• METTL1's effect on XPO5 localization and miRNA export was independent of its m7G methyltransferase activity.
• METTL1 promotes ERK-mediated phosphorylation of XPO5, enhancing its nuclear retention.

Conclusions:

• METTL1 has a non-canonical function in regulating XPO5 subcellular localization and pre-miRNA export.
• This mechanism controls miRNA maturation and extends METTL1's known functions beyond m7G methylation.