Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability

Abstract

FtsJ RNA 2′-O-methyltransferase 1 (FTSJ1) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2′-O-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient–derived cells. Loss of 2′-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.

Identification of a motif in Trm732 required for 2’-O-methylation of the tRNA anticodon loop by Trm7

“…Our finding that yeast Trm732 and human THADA variants with a mutated motif 2 lack tRNA activity make it possible to determine if the thermogenesis phenotype in D. melanogaster THADA mutants (51) is due to lack of tRNA modification activity or to an as yet uncharacterized protein activity. Likewise, the recent finding that human WDR6 is required for Nm 34 activity in human cells (43), that it is required for in vitro activity (46), and that it forms a complex with FTSJ1 (43,46) further shows the conserved and critical role of Trm734/WDR6 proteins in tRNA modification. Further experiments using THADA and WDR6 variants with impaired tRNA modification activity could help clarify the role of these proteins in other biological processes.…”

“…Human cell lines lacking FTSJ1 exhibit a growth defect that is exacerbated in the presence of the translation inhibitor paromomycin (43), and are more sensitive to vaccinia virus infection (35,44). Mice lacking FTSJ1 show impaired learning, anxiety-like behavior, increased sensitivity to pain, metabolic differences, and other phenotypes (45,46). The identity of the hypomodified tRNA(s) that causes these phenotypes in humans and mice lacking FTSJ1 is likely tRNA Phe , because loss of FTSJ1 causes a reduction in steady-state levels of tRNA Phe in the brain of mice (46), and because decoding of Phe codons, and in particular UUU, is perturbed in both mice and in cultured human cells (43,46).…”

“…Mice lacking FTSJ1 show impaired learning, anxiety-like behavior, increased sensitivity to pain, metabolic differences, and other phenotypes (45,46). The identity of the hypomodified tRNA(s) that causes these phenotypes in humans and mice lacking FTSJ1 is likely tRNA Phe , because loss of FTSJ1 causes a reduction in steady-state levels of tRNA Phe in the brain of mice (46), and because decoding of Phe codons, and in particular UUU, is perturbed in both mice and in cultured human cells (43,46). Interestingly, in Drosophila melanogaster , there are two Trm7/FTSJ1 paralogs, one of which modifies position 32 on substrate tRNAs, and one of which modifies position 34 on substrates.…”

“…Likewise, D. melanogaster has a Trm732/THADA homolog (47), but the role of this protein in Cm 32 modification has not been determined. The Trm734 homolog in humans is WDR6, which forms a complex with FTSJ1 and is required with FTSJ1 to form Gm 34 on tRNA Phe both in cells and in vitro (43,46). Although the precise roles of Trm732 and Trm734 in tRNA methylation are not known, analysis of the recently solved crystal structure of the yeast Trm7-Trm734 complex suggests that Trm734 is required to correctly position the substrate tRNA onto the Trm7-Trm734 enzyme (48).…”

From Recoding to Peptides for MHC Class I Immune Display: Enriching Viral Expression, Virus Vulnerability and Virus Evasion

“…The presentation of aberrant trans-frame peptides was detected, including from patient samples, with implications for immune recognition [ 193 ]. Limitation of specific fully functional tRNA is known in various other human diseases [ 194 , 195 ], and there is reduced supply in certain brain cells [ 196 ]. In some cases, there is known or suspected relevance to the generation of frameshift-derived peptides.…”