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.

The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism / Guiducci, Giulia; Paone, Alessio; Tramonti, Angela; Giardina, Giorgio; Rinaldo, Serena; Bouzidi, Amani; Magnifico, Maria C; Marani, Marina; Menendez, Javier A; Fatica, Alessandro; Macone, Alberto; Armaos, Alexandros; Tartaglia, Gian G; Contestabile, Roberto; Paiardini, Alessandro; Cutruzzolà, Francesca. - In: NUCLEIC ACIDS RESEARCH. - ISSN 0305-1048. - (2019), pp. 1-16. [10.1093/nar/gkz129]

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

Guiducci, Giulia;Paone, Alessio;Tramonti, Angela;Giardina, Giorgio;Rinaldo, Serena;Bouzidi, Amani;Magnifico, Maria C;Marani, Marina;Fatica, Alessandro;Macone, Alberto;Tartaglia, Gian G;Contestabile, Roberto;Paiardini, Alessandro;Cutruzzolà, Francesca
2019

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.
2019
metabolism; RNA binding protein; serine
01 Pubblicazione su rivista::01a Articolo in rivista
The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism / Guiducci, Giulia; Paone, Alessio; Tramonti, Angela; Giardina, Giorgio; Rinaldo, Serena; Bouzidi, Amani; Magnifico, Maria C; Marani, Marina; Menendez, Javier A; Fatica, Alessandro; Macone, Alberto; Armaos, Alexandros; Tartaglia, Gian G; Contestabile, Roberto; Paiardini, Alessandro; Cutruzzolà, Francesca. - In: NUCLEIC ACIDS RESEARCH. - ISSN 0305-1048. - (2019), pp. 1-16. [10.1093/nar/gkz129]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1244108
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