Cedars-Sinai Van Eyk Lab - LARP1_Paper

S-Adenosylmethionine Depletion Activates La Ribonucleoprotein Domain Family Member 1 to Induce Protein Translation

  • Organism: Homo sapiens, Mus musculus
  • Instrument: Orbitrap Fusion Lumos,TripleTOF 6600
  • SpikeIn: No
  • Keywords: NASH, liver, phospho, DIA, DDA, CDK2, Nonalcoholic Steatohepatitis, Hepatocellular carcinoma
S-adenosylmethionine (SAMe) is the principal methyl donor synthesized by methionine adenosyltransferase 1A (MAT1A)-encoded enzyme in the liver. Mice lacking Mat1a have hepatic SAMe depletion, spontaneous development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). To understand how SAMe depletion drives liver pathologies we performed phospho-proteomics in Mat1a knockout (KO) mice livers and the most striking change was hyperphosphorylation of La-Related Protein 1 (LARP1), which in the unphosphorylated form negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in the KO livers. We identified LARP1-T449 as a novel, SAMe-sensitive phospho-site of cyclin-dependent kinase 2. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC. Our results reveal a novel SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.  
Created on 6/24/20, 10:47 PM
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