TARS2

TARS2 is a mitochondrial threonyl-tRNA synthetase that supports mitochondrial translation and, separately, acts as a threonine sensor coupling nutrient availability to mTORC1 signaling (PMID:24827421, PMID:33340489). In its canonical role, TARS2 charges mitochondrial tRNAThr and clears mischarged Ser-tRNAThr, and pathogenic mutations that reduce TARS2 protein levels and aminoacylation function lower mitochondrial threonyl-tRNA and impair mitochondrial respiration, a defect rescued by re-expression of wild-type TARS2 in patient fibroblasts (PMID:24827421, PMID:34508595). Beyond aminoacylation, TARS2 interacts with inactive Rag GTPases—particularly GTP-loaded RagC—to promote GTP-loading of RagA and thereby activate mTORC1 in response to threonine, an effect specific to TARS2 and not shared by the cytoplasmic enzyme TARS (PMID:33340489). This signaling function maps to the TARS2 301–381 region, where pathogenic variants disrupt Rag binding and mTORC1 activation, with a zebrafish tars2 model recapitulating the human phenotype and downstream mTORC1 dysregulation (PMID:37454282). Excess TARS2 in cardiomyocytes perturbs mitochondrial homeostasis and drives ROS-dependent apoptosis, whereas its inhibition restores mitochondrial function and cardiac performance (PMID:42048853).

1. 2014 High

   Established that TARS2 is required for mitochondrial respiration via its role in mitochondrial threonyl-tRNA charging, linking loss-of-function variants to a respiratory chain defect.

   Evidence Whole-exome sequencing, protein and tRNA quantification, and rescue by wild-type transcript in patient fibroblasts

   PMID:24827421

   Open questions at the time

   • Did not resolve the editing/deacylation activity of the enzyme
   • Did not address any extra-translational function
2. 2020 High

   Revealed a moonlighting function distinct from aminoacylation: TARS2 senses threonine and activates mTORC1 through Rag GTPase engagement, separating this role from the cytoplasmic synthetase.

   Evidence Reciprocal Co-IP with Rag GTPases, RagA GTP-loading assays, and TARS2 knockout cells with mTORC1 readouts; TARS negative control

   PMID:33340489

   Open questions at the time

   • Structural basis of the TARS2–RagC interaction not defined
   • Whether aminoacylation and Rag-binding functions are mutually exclusive not resolved
3. 2022 Medium

   Defined the dual catalytic role of TARS2 in generating Thr-tRNAThr and clearing mischarged Ser-tRNAThr, and showed pathogenic variants act by destabilizing the protein or impairing aminoacylation.

   Evidence Aminoacylation and protein stability assays with homology modeling of pathogenic variants

   PMID:34508595

   Open questions at the time

   • Editing activity inferred without full reconstitution
   • Single-lab functional characterization
4. 2023 Medium

   Mapped the Rag-binding determinant to residues 301–381 and demonstrated in vivo that disrupting this interaction dysregulates mTORC1 signaling.

   Evidence In vitro Rag-binding assays of TARS2 variants and a zebrafish tars2 loss-of-function model with mTORC1 target analysis

   PMID:37454282

   Open questions at the time

   • Domain mapping from a single lab
   • Relative contribution of translation vs mTORC1 defects to phenotype not dissected
5. 2026 Medium

   Linked TARS2 dosage to mitochondrial ROS and cardiomyocyte apoptosis, indicating that excess TARS2 is pathogenic in cardiac tissue.

   Evidence Gain- and loss-of-function in cardiomyocytes with mitochondrial ROS, apoptosis, and cardiac function readouts

   PMID:42048853

   Open questions at the time

   • Mechanism connecting TARS2 overexpression to ROS not defined
   • Single-lab study with limited methodological detail

• How the aminoacylation and mTORC1-signaling functions of TARS2 are mechanistically coordinated, and the structural basis of Rag GTPase engagement, remain unresolved.
• No structural model of the TARS2–Rag complex
• Whether threonine binding to the catalytic site gates Rag interaction unknown