| Autor: |
Hogan, Caley A, Gratz, Scott J, Dumouchel, Jennifer L, Thakur, Rajan S, Delgado, Ambar, Lentini, Jenna M, Madhwani, Kimberly R, Fu, Dragony, O'Connor‐Giles, Kate M |
| Zdroj: |
EMBO Reports; 10/9/2023, Vol. 24 Issue 10, p1-17, 17p |
| Abstrakt: |
Nervous system function rests on the formation of functional synapses between neurons. We have identified TRMT9B as a new regulator of synapse formation and function in Drosophila. TRMT9B has been studied for its role as a tumor suppressor and is one of two metazoan homologs of yeast tRNA methyltransferase 9 (Trm9), which methylates tRNA wobble uridines. Whereas Trm9 homolog ALKBH8 is ubiquitously expressed, TRMT9B is enriched in the nervous system. However, in the absence of animal models, TRMT9B's role in the nervous system has remained unstudied. Here, we generate null alleles of TRMT9B and find it acts postsynaptically to regulate synaptogenesis and promote neurotransmission. Through liquid chromatography‐mass spectrometry, we find that ALKBH8 catalyzes canonical tRNA wobble uridine methylation, raising the question of whether TRMT9B is a methyltransferase. Structural modeling studies suggest TRMT9B retains methyltransferase function and, in vivo, disruption of key methyltransferase residues blocks TRMT9B's ability to rescue synaptic overgrowth, but not neurotransmitter release. These findings reveal distinct roles for TRMT9B in the nervous system and highlight the significance of tRNA methyltransferase family diversification in metazoans. Synopsis: The tRNA methyltransferase family has expanded in animals, yet the function of more recently evolved members is unknown. This study shows that TRMT9B regulates synaptic growth and function, likely through both methyltransferase‐dependent and methyltransferase‐independent mechanisms, without significantly affecting tRNA methylation. TRMT9B acts postsynaptically to regulate synaptic growth and promote neurotransmitter release.TRMT9B maintains all key methyltransferase residues and tertiary structure, but is not required for global tRNA wobble uridine methylation.Mutating conserved methyltransferase residues disrupts TRMT9B's ability to regulate synaptic growth, but not neurotransmission, consistent with newly evolved functions. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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