The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism

Nucleic Acids Research
Giulia GuiducciFrancesca Cutruzzolà

Abstract

Enzymes of intermediary metabolism are often reported to have moonlighting functions as RNA-binding proteins and have regulatory roles beyond their primary activities. Human serine hydroxymethyltransferase (SHMT) is essential for the one-carbon metabolism, which sustains growth and proliferation in normal and tumour cells. Here, we characterize the RNA-binding function of cytosolic SHMT (SHMT1) in vitro and using cancer cell models. We show that SHMT1 controls the expression of its mitochondrial counterpart (SHMT2) by binding to the 5'untranslated region of the SHMT2 transcript (UTR2). Importantly, binding to RNA is modulated by metabolites in vitro and the formation of the SHMT1-UTR2 complex inhibits the serine cleavage activity of the SHMT1, without affecting the reverse reaction. Transfection of UTR2 in cancer cells controls SHMT1 activity and reduces cell viability. We propose a novel mechanism of SHMT regulation, which interconnects RNA and metabolites levels to control the cross-talk between cytosolic and mitochondrial compartments of serine metabolism.

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Citations

Apr 11, 2020·Cancers·Zhixing WangXiaozhong Peng
Sep 4, 2020·Molecular Cancer Therapeutics·Aamod S DekhneLarry H Matherly
Jan 26, 2021·Biochemical Society Transactions·Jeffrey M SmithAndrew I Webb
Jan 30, 2021·Nature Metabolism·Shauni L GeeraertsKim R Kampen
Apr 17, 2021·ACS Pharmacology & Translational Science·Christine R CuthbertsonNouri Neamati
Jun 11, 2021·Biochemical Society Transactions·Nicole J Curtis, Constance J Jeffery
Jun 18, 2021·Computational and Structural Biotechnology Journal·Michele MontiGian Gaetano Tartaglia
Oct 26, 2021·The FEBS Journal·Sharon SpizzichinoFrancesca Cutruzzolà
Dec 7, 2021·Frontiers in Immunology·Nordin D ZandhuisMonika C Wolkers

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Methods Mentioned

BETA
PCR
Protein Assay
transfection

Software Mentioned

omiXcore
Ensembl
Global Score
PRISM
GraphPad

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