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A Catalytic Null Splice Variant of Human Leucyl‐tRNA Synthetase with Enhanced Non‐Canonical Function
Author(s) -
Forsyth Connor Mackenzie,
Baymiller Maxwell,
Martinis Susan A.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.526.31
Subject(s) - biology , aminoacyl trna synthetase , aminoacylation , mtorc1 , rna splicing , transfer rna , amino acyl trna synthetases , microbiology and biotechnology , protein biosynthesis , amino acid , rna , translation (biology) , gene , genetics , computational biology , signal transduction , messenger rna , pi3k/akt/mtor pathway
At the center of translation are the ancient and essential aminoacyl‐tRNA synthetases (AARS). These proteins set the genetic code by attaching amino acids to their cognate tRNAs with very high accuracy. Over a lengthy evolutionary time, AARS have developed functions beyond aminoacylation through the addition of new domains and repurposing of existing structural motifs. Non‐canonical functions of AARS are especially widespread in eukaryotes and range from cell signaling to transcription and translation regulation. For example, human cytoplasmic leucyl‐tRNA synthetase (LeuRS) has been adapted as an intracellular leucine sensor for the mammalian target of the rapamycin complex 1 (mTORC1) master regulatory pathway (Han, 2012). Ten alternatively‐spliced variants of cytoplasmic LeuRS were identified in humans using RNA Seq (Lo, 2014). It is possible that each of these splice variants contributes to novel and idiosyncratic functions. We have found that one of these variants, LeuRS AS04, is overexpressed in both Jurkat T cells and peripheral blood mononuclear cells (PBMC), suggesting a potential immune‐cell specific role. Despite the absence of key catalytic residues, LeuRS AS04 is a potent and specific activator of mTORC1. In particular, downstream phosphorylation of mTORC1 target ribosomal protein S6 kinase beta‐1 (p70S6K1) was significantly enhanced in cells overexpressing AS04 compared to those overexpressing full‐length LeuRS. We hypothesize that this alternately spliced LeuRS variant might have evolved to enhance and regulate the non‐canonical function of LeuRS‐dependent mTORC1 signaling. Support or Funding Information W.M. Keck Foundation Biomedical Research Grant This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .