title: Nudt3 is an mRNA decapping enzyme that modulates cell migration.
abstract: Removal of the 5'-end 7-methylguanosine cap structure is a critical step in the highly regulated process of mRNA decay. The Nudix hydrolase, Dcp2, was identified as a first decapping enzyme and subsequently shown to preferentially modulate stability of only a subset of mRNAs. This observation led to the hypothesis that mammalian cells possess multiple decapping enzymes that may function in distinct pathways. Here we report Nudt3 is a Nudix protein that possesses mRNA decapping activity in cells and is a modulator of MCF-7 breast cancer cell migration. Reduction of Nudt3 protein levels in MCF-7 cells promotes increased cell migration and corresponding enhanced filopodia extensions. Importantly, this phenotype was reversed by complementation with wild type, but not catalytically inactive Nudt3 protein indicating Nudt3 decapping activity normally functions to control cell migration. Genome-wide analysis of Nudt3 compromised cells identified elevated levels of transcripts involved in cell motility including integrin β6, lipocalin-2, and fibronectin. The observed increase in mRNA abundance was dependent on Nudt3 decapping activity where integrin β6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 knockdown cells was mediated through the extracellular integrin β6 and fibronectin protein nexus. We conclude that Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Grudzien-Nogalska
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Xinfu
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Man-Gen
authors.initials: MG
authors.lastname: Song
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA kiledjian@biology.rutgers.edu.
authors.forename: Megerditch
authors.initials: M
authors.lastname: Kiledjian
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D015536:Down-Regulation; D004722:Endoribonucleases; D005353:Fibronectins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D061986:MCF-7 Cells
chemical_list: D005353:Fibronectins; D039641:Integrin beta Chains; C072170:integrin beta6; C030052:mRNA decapping enzymes; D004722:Endoribonucleases; D017766:Acid Anhydride Hydrolases; C116368:diphosphoinositol polyphosphate phosphohydrolase
keywords: Nudt3; cell motility; fibronectin; integrin β6; mRNA decapping; mRNA stability