Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in YTHDF2-dependent manner

The methyltransferase-like 3 (Mett13) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m(6)A) modification, which plays an important role in gene post-transcription modulation. Although RNA m(6)A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m(6)A level and m(6)A writer Mett13 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mett13 elevated the levels of m 6 A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mett13 reversed a loss of m(6)A in Teti mRNA and blocked the CFAinduced increase of TETI in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m(6)A reader, stabilized upregulation of spinal TET1 because of the reduction of Teti mRNA decay by the binding to m(6)A in Teti mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.

Automated summary

The study reveals that downregulation of spinal METTL3 and coordination with YTHDF2 contribute to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons. Manipulating Mett13 levels can affect pain behavior, and decreased levels of YTHDF2 can lead to increased TET1 levels in the spinal cord and influence pain regulation.