Noncanonical function of glutamyl-prolyl-tRNA synthetase: Gene-specific silencing of translation

Prabha Sampath; Barsanjit Mazumder; Vasudevan Seshadri; Carri A. Gerber; Laurent Chavatte; Michael Kinter; Shu M. Ting; J. David Dignam; Sunghoon Kim; Donna M. Driscoll; Paul L. Fox

doi:10.1016/j.cell.2004.09.030

Noncanonical function of glutamyl-prolyl-tRNA synthetase: Gene-specific silencing of translation

Prabha Sampath, Barsanjit Mazumder, Vasudevan Seshadri, Carri A. Gerber, Laurent Chavatte, Michael Kinter, Shu M. Ting, J. David Dignam, Sunghoon Kim, Donna M. Driscoll, Paul L. Fox

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

203 Citations (Scopus)

Abstract

Aminoacyl tRNA synthetases (ARS) catalyze the ligation of amino acids to cognate tRNAs. Chordate ARSs have evolved distinctive features absent from ancestral forms, including compartmentalization in a multisynthetase complex (MSC), noncatalytic peptide appendages, and ancillary functions unrelated to aminoacylation. Here, we show that glutamyl-prolyl-tRNA synthetase (GluProRS), a bifunctional ARS of the MSC, has a regulated, noncanonical activity that blocks synthesis of a specific protein. GluProRS was identified as a component of the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex by RNA affinity chromatography using the ceruloplasmin (Cp) GAIT element as ligand. In response to IFN-γ, GluProRS is phosphorylated and released from the MSC, binds the Cp 3′-untranslated region in an mRNP containing three additional proteins, and silences Cp mRNA translation. Thus, GluProRS has divergent functions in protein synthesis: in the MSC, its aminoacylation activity supports global translation, but translocation of GluProRS to an inflammation-responsive mRNP causes gene-specific translational silencing.

Original language	English
Pages (from-to)	195-208
Number of pages	14
Journal	Cell
Volume	119
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2004.09.030
Publication status	Published - 2004 Oct 15

Bibliographical note

Funding Information:
This work was supported by grants HL29582, HL67725, and HL76491 from the NIH (to P.L.F.); by an AHA Predoctoral Fellowship, Ohio Valley Affiliate (to P.S.); and by a Scientist Development Grant from the AHA, National Affiliate (to B.M.). We appreciate the assistance of Ratan Maitra in the Lerner Research Institute Virus Core Facility for expression of NSAP1. We are grateful to Ira Wool and Paul Schimmel for helpful discussions. We acknowledge Gideon Dreyfuss for the generous gift of anti-hnRNP Q/R and SP2/O antibodies. None of the authors have any financial conflict of interest with the information in this manuscript.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2004.09.030

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@article{19f15635a5854f249664bfbf370bd199,

title = "Noncanonical function of glutamyl-prolyl-tRNA synthetase: Gene-specific silencing of translation",

abstract = "Aminoacyl tRNA synthetases (ARS) catalyze the ligation of amino acids to cognate tRNAs. Chordate ARSs have evolved distinctive features absent from ancestral forms, including compartmentalization in a multisynthetase complex (MSC), noncatalytic peptide appendages, and ancillary functions unrelated to aminoacylation. Here, we show that glutamyl-prolyl-tRNA synthetase (GluProRS), a bifunctional ARS of the MSC, has a regulated, noncanonical activity that blocks synthesis of a specific protein. GluProRS was identified as a component of the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex by RNA affinity chromatography using the ceruloplasmin (Cp) GAIT element as ligand. In response to IFN-γ, GluProRS is phosphorylated and released from the MSC, binds the Cp 3′-untranslated region in an mRNP containing three additional proteins, and silences Cp mRNA translation. Thus, GluProRS has divergent functions in protein synthesis: in the MSC, its aminoacylation activity supports global translation, but translocation of GluProRS to an inflammation-responsive mRNP causes gene-specific translational silencing.",

author = "Prabha Sampath and Barsanjit Mazumder and Vasudevan Seshadri and Gerber, {Carri A.} and Laurent Chavatte and Michael Kinter and Ting, {Shu M.} and Dignam, {J. David} and Sunghoon Kim and Driscoll, {Donna M.} and Fox, {Paul L.}",

note = "Funding Information: This work was supported by grants HL29582, HL67725, and HL76491 from the NIH (to P.L.F.); by an AHA Predoctoral Fellowship, Ohio Valley Affiliate (to P.S.); and by a Scientist Development Grant from the AHA, National Affiliate (to B.M.). We appreciate the assistance of Ratan Maitra in the Lerner Research Institute Virus Core Facility for expression of NSAP1. We are grateful to Ira Wool and Paul Schimmel for helpful discussions. We acknowledge Gideon Dreyfuss for the generous gift of anti-hnRNP Q/R and SP2/O antibodies. None of the authors have any financial conflict of interest with the information in this manuscript.",

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language = "English",

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T1 - Noncanonical function of glutamyl-prolyl-tRNA synthetase

T2 - Gene-specific silencing of translation

AU - Sampath, Prabha

AU - Mazumder, Barsanjit

AU - Seshadri, Vasudevan

AU - Gerber, Carri A.

AU - Chavatte, Laurent

AU - Kinter, Michael

AU - Ting, Shu M.

AU - Dignam, J. David

AU - Kim, Sunghoon

AU - Driscoll, Donna M.

AU - Fox, Paul L.

N1 - Funding Information: This work was supported by grants HL29582, HL67725, and HL76491 from the NIH (to P.L.F.); by an AHA Predoctoral Fellowship, Ohio Valley Affiliate (to P.S.); and by a Scientist Development Grant from the AHA, National Affiliate (to B.M.). We appreciate the assistance of Ratan Maitra in the Lerner Research Institute Virus Core Facility for expression of NSAP1. We are grateful to Ira Wool and Paul Schimmel for helpful discussions. We acknowledge Gideon Dreyfuss for the generous gift of anti-hnRNP Q/R and SP2/O antibodies. None of the authors have any financial conflict of interest with the information in this manuscript.

PY - 2004/10/15

Y1 - 2004/10/15

N2 - Aminoacyl tRNA synthetases (ARS) catalyze the ligation of amino acids to cognate tRNAs. Chordate ARSs have evolved distinctive features absent from ancestral forms, including compartmentalization in a multisynthetase complex (MSC), noncatalytic peptide appendages, and ancillary functions unrelated to aminoacylation. Here, we show that glutamyl-prolyl-tRNA synthetase (GluProRS), a bifunctional ARS of the MSC, has a regulated, noncanonical activity that blocks synthesis of a specific protein. GluProRS was identified as a component of the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex by RNA affinity chromatography using the ceruloplasmin (Cp) GAIT element as ligand. In response to IFN-γ, GluProRS is phosphorylated and released from the MSC, binds the Cp 3′-untranslated region in an mRNP containing three additional proteins, and silences Cp mRNA translation. Thus, GluProRS has divergent functions in protein synthesis: in the MSC, its aminoacylation activity supports global translation, but translocation of GluProRS to an inflammation-responsive mRNP causes gene-specific translational silencing.

AB - Aminoacyl tRNA synthetases (ARS) catalyze the ligation of amino acids to cognate tRNAs. Chordate ARSs have evolved distinctive features absent from ancestral forms, including compartmentalization in a multisynthetase complex (MSC), noncatalytic peptide appendages, and ancillary functions unrelated to aminoacylation. Here, we show that glutamyl-prolyl-tRNA synthetase (GluProRS), a bifunctional ARS of the MSC, has a regulated, noncanonical activity that blocks synthesis of a specific protein. GluProRS was identified as a component of the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex by RNA affinity chromatography using the ceruloplasmin (Cp) GAIT element as ligand. In response to IFN-γ, GluProRS is phosphorylated and released from the MSC, binds the Cp 3′-untranslated region in an mRNP containing three additional proteins, and silences Cp mRNA translation. Thus, GluProRS has divergent functions in protein synthesis: in the MSC, its aminoacylation activity supports global translation, but translocation of GluProRS to an inflammation-responsive mRNP causes gene-specific translational silencing.

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JF - Cell

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Noncanonical function of glutamyl-prolyl-tRNA synthetase: Gene-specific silencing of translation

Abstract

Bibliographical note

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