S-adenosylmethionine inhibits la ribonucleoprotein domain family member 1 in murine liver and human liver cancer cells.

Abstract

BACKGROUND AND AIMS:

Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion and develop NASH and HCC spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, characterizing the phospho-proteome and determining whether they contribute to liver pathology remain open for study. Our study aimed to provide this knowledge.

APPROACH AND RESULTS:

We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found that the most striking change was hyperphosphorylation and increased content 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 KO livers. Translation of TOP mRNAs ribosomal protein S3 and ribosomal protein L18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1-overexpression-mediated increase in translation. 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.

CONCLUSIONS:

Our results reveal a SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.

• Authors: Komal Ramani, Aaron E Robinson, Joshua Berlind, Wei Fan, Aushinie Abeynayake, Aleksandra Binek, Lucía Barbier-Torres, Mazen Noureddin, Nicholas N Nissen, Zehra Yildirim, Ebru Erbay, José M Mato, Jennifer E Van Eyk, Shelly C Lu
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 75 Issue 2 Pg. 280-296 (02 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34449924 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Association for the Study of Liver Diseases.

Chemical References

• Autoantigens
• Larp1 protein, mouse
• Oligonucleotides
• RNA, Messenger
• RNA-Binding Proteins
• RPS3 protein, human
• Ribonucleoproteins
• Ribosomal Proteins
• SS-B antigen
• ribosomal protein L18
• S-Adenosylmethionine
• Mat1a protein, mouse
• Methionine Adenosyltransferase
• mTOR protein, mouse
• TOR Serine-Threonine Kinases
• CDK2 protein, human
• Cdk2 protein, mouse
• Cyclin-Dependent Kinase 2

Topics

• Animals
• Autoantigens (metabolism)
• Carcinoma, Hepatocellular (metabolism)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Cyclin-Dependent Kinase 2 (genetics, immunology, metabolism)
• Humans
• Liver Neoplasms (metabolism)
• Methionine Adenosyltransferase (genetics)
• Mice
• Mice, Knockout
• Mutation
• Non-alcoholic Fatty Liver Disease (metabolism)
• Oligonucleotides (genetics)
• Phosphorylation (drug effects)
• Protein Biosynthesis (drug effects)
• Proteomics
• RNA, Messenger (metabolism)
• RNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Ribonucleoproteins (antagonists & inhibitors, metabolism)
• Ribosomal Proteins (genetics)
• S-Adenosylmethionine (metabolism, pharmacology)
• TOR Serine-Threonine Kinases (metabolism)