LARS1

LARS1 (leucyl-tRNA synthetase 1) is a cytoplasmic enzyme whose function extends beyond aminoacylation to act as an intracellular leucine sensor that gates mTORC1 activity and thereby controls cell growth, autophagy, and lipid metabolism (PMID:36960627, PMID:40815951). The human leuS gene maps to chromosome 5q and functionally complements a temperature-sensitive leuS lethal mutation in hamster cells, establishing its conserved essential role in protein synthesis (PMID:9732752, PMID:7177110). Across multiple cell types LARS1 activates mTORC1 to suppress autophagy and lipophagy: its knockdown induces autophagy and inhibits proliferation, invasion, and migration in thyroid cancer cells in an mTOR-dependent manner (PMID:40815951), and it suppresses lipophagy to drive lipid accumulation and epithelial-mesenchymal transition in tubular epithelial cells, with Lars1+/- mice showing reduced fibrosis (PMID:40397353). LARS1 abundance and activity are regulated post-translationally: USP7 deubiquitinates and stabilizes LARS1, while the mitochondrial-derived peptide MOTS-c competes with USP7 to promote LARS1 ubiquitination and proteasomal degradation (PMID:39321430), and lactylation at K970 under high-glucose conditions enhances mTORC1 activation to promote podocyte injury in diabetic kidney disease (PMID:40545110). In hypoxia, HIF-1α transcriptionally upregulates LARS1 and physically associates with it; LARS1-containing exosomes are transferred to recipient pancreatic cancer cells to activate mTOR and promote vasculogenic mimicry (PMID:39955826). Consistent with its role upstream of autophagy, a patient-derived biallelic LARS1 variant modeled in zebrafish causes enhanced autophagy and hepatic steatosis, rescued by autophagy or DGAT1 inhibition (PMID:38807157). The LARS1 inhibitor BC-LI-0186 paradoxically activates MAPK signaling, and combining it with MEK inhibition synergistically suppresses tumor growth (PMID:36960627).

1. 1982 Medium

   Establishing the chromosomal location and functional conservation of the human leuS gene confirmed it encodes a bona fide leucyl-tRNA synthetase essential for viability.

   Evidence Interspecific somatic cell hybrid complementation of a temperature-sensitive lethal leuS mutation and cytogenetic deletion mapping on chromosome 5

   PMID:7177110 PMID:9732752

   Open questions at the time

   • Did not characterize enzymatic mechanism or any non-canonical signaling function
   • Gene order established but regulatory elements not defined
2. 2008 Medium

   Loss-of-function established that LARS1 contributes to cancer cell growth and migration beyond housekeeping translation.

   Evidence siRNA knockdown in A549 lung cancer cells with transwell migration and soft-agar colony formation assays

   PMID:18446061

   Open questions at the time

   • No molecular mechanism linking LARS1 to migration identified
   • Did not distinguish aminoacylation from signaling roles
3. 2023 Medium

   Positioning LARS1 as a leucine sensor for mTORC1 activation provided a pharmacological handle and revealed compensatory MAPK signaling upon its inhibition.

   Evidence BC-LI-0186 inhibition with phospho-protein immunoblotting, RNA-seq, combination index analysis, and xenograft in NSCLC

   PMID:36960627

   Open questions at the time

   • Molecular basis of paradoxical MAPK activation not resolved
   • Direct sensing mechanism not structurally defined in this study
4. 2024 Medium

   Defining USP7 as a LARS1 deubiquitinase and MOTS-c as a competitor revealed how LARS1 protein stability is dynamically controlled.

   Evidence Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, and competition binding

   PMID:39321430

   Open questions at the time

   • Ubiquitin ligase for LARS1 not identified
   • Physiological triggers of MOTS-c–LARS1 competition unclear
5. 2024 Medium

   A patient-derived variant modeled in zebrafish placed LARS1 deficiency upstream of autophagy-driven hepatic lipid accumulation, linking the gene to a disease phenotype.

   Evidence larsb-I451F knock-in zebrafish with pharmacological autophagy and DGAT1 inhibition epistasis

   PMID:38807157

   Open questions at the time

   • Human disease causation rests on a model organism variant
   • Mechanism by which deficiency enhances autophagy not detailed
6. 2025 Medium

   Multiple disease contexts converged on LARS1–mTORC1 control of autophagy/lipophagy, with PTM (lactylation), transcriptional (HIF-1α), and exosomal regulation defining tissue-specific outputs.

   Evidence K970 lactylation proteomics and diabetic mouse siRNA; TGF-β1 tubular cells and Lars1+/- mice; HIF-1α Co-IP and exosome proteomics in pancreatic cancer; mTOR-agonist rescue in thyroid cancer

   PMID:39955826 PMID:40397353 PMID:40545110 PMID:40815951

   Open questions at the time

   • Whether RagD-mediated sensing underlies all these contexts not directly tested in each
   • Each finding from a single lab without independent replication

• How LARS1 structurally couples leucine occupancy to mTORC1 activation and which E3 ligase counteracts USP7 remain open.
• No structural model of LARS1 leucine-sensing in the corpus
• E3 ligase opposing USP7 unidentified
• RagD interaction not directly demonstrated in the timeline