Disease-associated mutations in a bifunctional aminoacyl-tRNA synthetase gene elicit the integrated stress response

Abstract

Aminoacyl-tRNA synthetases (ARSs) catalyze the charging of specific amino acids onto cognate tRNAs, an essential process for protein synthesis. Mutations in ARSs are frequently associated with a variety of human diseases. The human EPRS1 gene encodes a bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) with two catalytic cores and appended domains that contribute to nontranslational functions. In this study, we report compound heterozygous mutations in EPRS1, which lead to amino acid substitutions P14R and E205G in two patients with diabetes and bone diseases. While neither mutation affects tRNA binding or association of EPRS with the multisynthetase complex, E205G in the glutamyl-tRNA synthetase (ERS) region of EPRS is defective in amino acid activation and tRNAGlu charging. The P14R mutation induces a conformational change and altered tRNA charging kinetics in vitro. We propose that the altered catalytic activity and conformational changes in the EPRS variants sensitize patient cells to stress, triggering an increased integrated stress response (ISR) that diminishes cell viability. Indeed, patient-derived cells expressing the compound heterozygous EPRS show heightened induction of the ISR, suggestive of disruptions in protein homeostasis. These results have important implications for understanding ARS-associated human disease mechanisms and development of new therapeutics. Aminoacyl-tRNA synthetases (ARSs) catalyze the charging of specific amino acids onto cognate tRNAs, an essential process for protein synthesis. Mutations in ARSs are frequently associated with a variety of human diseases. The human EPRS1 gene encodes a bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) with two catalytic cores and appended domains that contribute to nontranslational functions. In this study, we report compound heterozygous mutations in EPRS1, which lead to amino acid substitutions P14R and E205G in two patients with diabetes and bone diseases. While neither mutation affects tRNA binding or association of EPRS with the multisynthetase complex, E205G in the glutamyl-tRNA synthetase (ERS) region of EPRS is defective in amino acid activation and tRNAGlu charging. The P14R mutation induces a conformational change and altered tRNA charging kinetics in vitro. We propose that the altered catalytic activity and conformational changes in the EPRS variants sensitize patient cells to stress, triggering an increased integrated stress response (ISR) that diminishes cell viability. Indeed, patient-derived cells expressing the compound heterozygous EPRS show heightened induction of the ISR, suggestive of disruptions in protein homeostasis. These results have important implications for understanding ARS-associated human disease mechanisms and development of new therapeutics. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis across all domains of life, ensuring translational fidelity and maintenance of protein homeostasis by aminoacylating tRNAs with their cognate amino acids. For each amino acid, with a few exceptions in some bacteria and archaea, a specific ARS catalyzes tRNA aminoacylation in two steps: (1) amino acid activation and formation of an aminoacyl-adenylate (aa-AMP) and (2) transfer of the amino acid onto the 3′ end of tRNA (1Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google Scholar). In addition to a catalytic domain that directs the aminoacylation or charging reaction, the majority of ARSs contain an anticodon-binding domain that interacts specifically with the cognate tRNA substrate. Many eukaryotic ARSs have appended domains with no apparent function in tRNA charging (2Guo M. Schimmel P. Essential nontranslational functions of tRNA synthetases.Nat. Chem. Biol. 2013; 9: 145-153Crossref PubMed Scopus (241) Google Scholar). For example, human glutamyl-prolyl tRNA synthetase (EPRS) is a unique bifunctional ARS, consisting of glutamyl-tRNA synthetase (ERS) and prolyl-tRNA synthetase (PRS) catalytic domains, an appended glutathione-S-transferase-like (GST-l) domain on the N-terminus of ERS and three WHEP domains in the linker region connecting the two catalytic cores (Fig. 1A) (3Ray P.S. Fox P.L. Origin and evolution of glutamyl-prolyl tRNA synthetase WHEP domains reveal evolutionary relationships within Holozoa.PLoS One. 2014; 9e98493Crossref PubMed Scopus (16) Google Scholar). The evolutionary fusion between the ERS and PRS genes is thought to have occurred prior to the appearance of animals, and the emergence of a bifunctional EPRS is suggested to have a metabolic advantage over separated ERS and PRS genes (4Eswarappa S.M. Potdar A.A. Sahoo S. Sankar S. Fox P.L. Metabolic origin of the fused aminoacyl-tRNA synthetase, glutamyl-prolyl-tRNA synthetase.J. Biol. Chem. 2018; 293: 19148-19156Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Human EPRS is normally localized to a cytoplasmic high-molecular-weight multisynthetase complex (MSC) that is composed of seven other ARSs and three ARS-complex interacting multifunctional proteins (AIMPs) designated as AIMP1, AIMP2, and AIMP3. The GST-l domains of EPRS, methionyl-tRNA synthetase (MetRS), AIMP2, and AIMP3 form a complex that is critical for the assembly of the MSC (5Cho H.Y. Maeng S.J. Cho H.J. Choi Y.S. Chung J.M. Lee S. Kim H.K. Kim J.H. Eom C.Y. Kim Y.G. Guo M. Jung H.S. Kang B.S. Kim S. 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M. of a human aminoacyl-tRNA synthetase 2015; PubMed Scopus Google Scholar, The of tRNA synthetases in and 2018; PubMed Scopus Google Scholar, mechanisms of aminoacyl-tRNA synthetase mutations in and human 26: PubMed Scopus Google mutations in the PRS of human EPRS1 gene with and aminoacylation patient-derived suggested PRS activity with M. mutations in EPRS, the synthetase, a J. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). aminoacylation of tRNAs and associated disruptions in protein homeostasis the integrated stress response (ISR) mechanisms of aminoacyl-tRNA synthetase mutations in and human 26: PubMed Scopus Google Scholar, with and translational PubMed Scopus Google Scholar, of in translational and to Biol. 2018; PubMed Scopus Google Scholar). The induces of genes in protein and which to protein homeostasis. with and protein the of EPRS and other ARSs increased by the of in translational and to Biol. 2018; PubMed Scopus Google Scholar, J. J. J. S. M. M.A. protein synthesis to cell Cell Biol. 2013; PubMed Scopus Google Scholar, translation induces of Biol. 2014; PubMed Scopus Google Scholar, and translational in PubMed Scopus Google Scholar, of the glutamyl-prolyl-tRNA synthetase gene EPRS of with Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). While induction of the is important for to stress and of protein induction of genes cell S.J. C.Y. S. induces by protein synthesis and in the PubMed Scopus Google Scholar, the mechanisms of by Cell Biol. PubMed Scopus Google Scholar, the function of in diabetes Full Text Full Text PDF PubMed Scopus (6) Google Scholar). we report of two with diabetes and bone compound heterozygous EPRS variants in P14R and E205G substitutions in the GST-l and ERS catalytic domains, mutations the function of EPRS in protein we and ERS proteins and their on and function in as as on MSC association in of gene induction in response to stress in patient-derived expressing results patient-derived EPRS and their with stress and on two with diabetes and bone M. associated with mutations in the PubMed Scopus Google two EPRS to and to (Fig. of the two mutations by are and are in the patients in their Human EPRS is in of human EPRS has been ERS and PRS domains have been and of PRS in amino acid activation and aminoacylation activity and aminoacyl-tRNA synthetase activity of Chem. Scopus Google Scholar). In ERS proteins with of the linker region and aminoacylation activity P. Fox P.L. of glutamyl-tRNA synthetase by appended WHEP domains.J. Biol. Chem. 2018; 293: Full Text Full Text PDF PubMed Scopus Google Scholar). In of an of human EPRS in the protein in this we two protein ERS which amino acid the of the ERS domain that are in a region prior to the WHEP domains, and with the and WHEP domains (Fig. The protein to in cells as a P. Fox P.L. of glutamyl-tRNA synthetase by appended WHEP domains.J. Biol. Chem. 2018; 293: Full Text Full Text PDF PubMed Scopus Google Scholar). The proteins to (Fig. to the of the ERS proteins in for each protein (Fig. for and are and which are to the the and and are of of proteins in These results are with the of synthetases M. The aminoacyl-tRNA synthetase PubMed Scopus Google and with of the EPRS as a of the PRS domains (5Cho H.Y. Maeng S.J. Cho H.J. Choi Y.S. Chung J.M. Lee S. Kim H.K. Kim J.H. Eom C.Y. Kim Y.G. Guo M. Jung H.S. Kang B.S. Kim S. Assembly of multi-tRNA synthetase complex via heterotetrameric glutathione transferase-homology domains.J. Biol. Chem. 2015; 290: 29313-29328Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, H.Y. Lee H.J. Choi Y.S. Kim Kim S. Kang B.S. assembly of a in human multi-tRNA synthetase complex via between glutathione transferase-homology domains and synthetase.J. Biol. PubMed Scopus Google Scholar). We the of proteins to to tRNA a binding and in 3′ ERS with a of for and a for (Fig. and that the of WHEP domains facilitates tRNA binding to the ERS aminoacylation of and tRNA that ERS in charging in human tRNAGlu (Fig. of and aminoacylation activity of for in of binding tRNAs and and or are to The results are the of three with in a new binding tRNAs and and or are to The results are the of three with to a of eukaryotic EPRS (Fig. and are is in the GST-l is in the ERS catalytic to the of binding (Fig. and We that are to a critical function in the of EPRS in tRNA and in this we the of mutations on ERS ERS proteins with P14R and E205G mutations and for tRNA in and and P14R and E205G to tRNAGlu with of and which are to that of (Fig. E205G to that of (Fig. and and E205G of the WHEP domains facilitates tRNA that the P14R and E205G mutations tRNAGlu binding and have no on the of the WHEP We the aminoacylation activity of the We aminoacylation tRNAGlu the of aminoacylation is to the catalytic The P14R of aminoacylation with a (Fig. In the E205G a in with is in with the that is the and is to in binding (Fig. We the amino acid activation of the enzymes For the of tRNA is for amino acid with and is the exceptions J.M. and acid synthetases of and of by Biol. Chem. Full Text PDF PubMed Google Scholar, The transfer acid synthetase of Biol. Chem. Full Text PDF PubMed Google Scholar, for and of aminoacyl-tRNA PubMed Scopus Google Scholar). a tRNAGlu with a 3′ end is in to the amino acid activation aminoacyl-adenylate by a aminoacyl-tRNA synthetase.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We the 3′ end of in tRNAGlu by by (Fig. of with and Scholar). The tRNA as (Fig. and for a of amino acid activation as by the formation of over (Fig. no amino acid activation for the P14R or E205G in the of (Fig. While this is for E205G which defective in tRNA the with the P14R that amino acid activation the the of formation that P14R the to catalyze it is that the P14R results in a amino acid activation on the of of this we that the P14R is defective in amino acid activation to the the activity of the P14R in we for tRNA aminoacylation for and P14R and by the of aminoacylation tRNA and the to the (Fig. The results are in the is by in the P14R with the The has a in an that is to a that is with the in 3 and for aminoacylation of by and P14R aminoacylation with tRNA and For tRNA and protein The are the of three with the in a new For aminoacylation with tRNA and For tRNA and protein The are the of three with the the in the between the and P14R we new for and of Biochem. 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Chem. 2015; 290: 29313-29328Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). cell that of the EPRS for and efficient EPRS (Fig. EPRS the mutations is of the we EPRS and which are to the in cells with EPRS and with a E205G EPRS interacts with the MSC scaffold proteins and AIMP3 to (Fig. the P14R EPRS in cells protein as by the of an protein (Fig. and AIMP3 for the P14R to the of The is the domain of EPRS, as it with the and is in a (Fig. on the is with a of human EPRS, which is in between the WHEP domain and PRS catalytic and to the The form of P14R EPRS in cells a of as it is in the of patient-derived cells expressing the EPRS (Fig. the in EPRS P14R protein a conformational in this that the protein to the of the mutations on ERS we to the and of and and proteins with and (Fig. an by as a function of to the and apparent and the (Fig. The and proteins have the two and for by protein to and the to and The are the of three with the in a new by protein to and the to and The are the of three with the The conformational between and a proteins with which on the of and or which on the of The by of the protein two of and (Fig. The E205G protein a as (Fig. In of the P14R and the in the of the (Fig. and and E205G a with a P14R and proteins over the (Fig. results that the P14R mutation a conformational in to altered of aminoacylation of tRNAs is critical for the fidelity of and in protein homeostasis and the with and translational PubMed Scopus Google Scholar, of in translational and to Biol. 2018; PubMed Scopus Google Scholar). While induction of the is for of stress and of protein of genes as to stress and cell S.J. C.Y. S. induces by protein synthesis and in the PubMed Scopus Google Scholar, the mechanisms of by Cell Biol. PubMed Scopus Google Scholar, the function of in diabetes Full Text Full Text PDF PubMed Scopus (6) Google Scholar). the of in patient-derived expressing the EPRS1 genes or cells with a of stress, and the of EPRS1, and with (Fig. In the of stress, patient-derived cells of EPRS and stress, the cells increased of EPRS and the other genes with The of EPRS, and proteins by in the patient-derived cells in the and of stress (Fig. and are stress, and a of and proteins in the EPRS cells with results that patient-derived cells expressing EPRS are to stress, gene in response to is a in the between the and EPRS the cells with for to and cell by the While cells to the stress the EPRS cells in cell with of cells of (Fig. These results that the catalytic associated with the EPRS sensitize cells to disruptions in protein to cell viability. Human ARS mutations have been associated with and and and liver and J. Human to cytoplasmic aminoacyl-tRNA and The the association of diabetes and The compound heterozygous mutations in the ERS domain of EPRS in two patients with diabetes and bone P14R and associated with human and the of mutations on ERS catalytic function in or on protein synthesis and homeostasis in We ERS proteins and that the E205G catalytic domain results in in amino acid activation and tRNAGlu charging. The P14R in the GST-l domain induces a protein conformational change and altered tRNA charging kinetics in vitro. The induction of the in patient-derived cells is with disruptions in protein homeostasis. M. mutations in EPRS, the synthetase, a J. 2018; Full Text Full Text PDF PubMed Scopus Google three mutations in the PRS domain of EPRS that with a disease associated with other human ARS suggests that mutations in the ERS domain contribute to changes and to stress, and that ERS variants in the patients in to with the PRS is that other patient mutations or in with the ERS mutations contribute to the bone and diabetes by the While no of human EPRS protein has been ERS of have been and of activity J. M. Fox P.L. of EPRS of translational Full Text Full Text PDF PubMed Scopus Google Scholar, P. Fox P.L. of glutamyl-tRNA synthetase by appended WHEP domains.J. Biol. Chem. 2018; 293: Full Text Full Text PDF PubMed Scopus Google Scholar). the protein linker in the and proteins that the linker region facilitates of the ERS catalytic proteins and aminoacylation activity (Fig. The WHEP domains tRNAGlu and in of in The WHEP domains to the of the ERS catalytic P. Fox P.L. of glutamyl-tRNA synthetase by appended WHEP domains.J. Biol. Chem. 2018; 293: Full Text Full Text PDF PubMed Scopus Google which lead to a for tRNA The P14R ERS tRNAGlu aminoacylation in the E205G is defective in charging EPRS gene is in the patient P14R EPRS is critical for tRNAGlu translation and cell viability. P14R ERS tRNA by the to a by the Indeed, we aminoacylation in the of which is for and P14R we formation for P14R with (Fig. These results that cells expressing EPRS variants have an to stress by amino acid and tRNA ERS is the ARSs that the of tRNA for amino acid activation (1Rubio Gomez M.A. Ibba M. Aminoacyl-tRNA synthetases.RNA. 2020; 26: 910-936Crossref PubMed Scopus (29) Google which for the amino acid transfer While the by which tRNA facilitates amino acid activation by some ARSs it has been that the of the of the 3′ M. S. S. of of activation on a of synthetase, and an J. PubMed Scopus (16) Google Scholar). a tRNA that is of is for formation in by which the amino acid transfer transfer in a aminoacyl-tRNA synthetase.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google or by a tRNA with a 3′ aminoacyl-adenylate by a aminoacyl-tRNA synthetase.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this study, we the 3′ of tRNAGlu by and a to amino acid transfer (Fig. The tRNA for a that the and of amino acid activation by a of formation for the (Fig. and to the of the the enzymes defective this and no formation (Fig. In the of this is of the to to the of this to the (Fig. The of formation for the P14R is to the of the The is the of the of the GST-l domain (5Cho H.Y. Maeng S.J. Cho H.J. Choi Y.S. Chung J.M. Lee S. Kim H.K. Kim J.H. Eom C.Y. Kim Y.G. Guo M. Jung H.S. Kang B.S. Kim S. Assembly of multi-tRNA synthetase complex via heterotetrameric glutathione transferase-homology domains.J. Biol. Chem. 2015; 290: 29313-29328Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). of to the by as is a that EPRS GST-l interacts with the MSC scaffold proteins and AIMP3 via two and and the other and (5Cho H.Y. Maeng S.J. Cho H.J. Choi Y.S. Chung J.M. Lee S. Kim H.K. Kim J.H. Eom C.Y. Kim Y.G. Guo M. Jung H.S. Kang B.S. Kim S. Assembly of multi-tRNA synthetase complex via heterotetrameric glutathione transferase-homology domains.J. Biol. Chem. 2015; 290: 29313-29328Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). We show that P14R EPRS of interacting with and that the The P14R mutation have conformational on the EPRS as suggested by altered ERS aminoacylation protein EPRS in and changes in the We that the P14R mutation the ERS catalytic the amino acid activation it for tRNA of ARSs is increased in cells in response to stress, as a that results in of protein synthesis translation induces of Biol. 2014; PubMed Scopus Google Scholar). 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S. P. is a of and an essential of for Full Text Full Text PDF PubMed Scopus Google Scholar, The amino acid is for of in 2020; PubMed Scopus Google Scholar, J. is essential for development to and PubMed Scopus Google Scholar). We show that patient cells the EPRS mutations P14R and E205G are to stress, as by and and protein to the of the the for stress, it is suggested that EPRS mutations that aminoacylation of tRNA protein synthesis and stress and induction in some activation of the in the EPRS cells the stress of the the function of in diabetes Full Text Full Text PDF PubMed Scopus (6) Google Scholar). In this to as the of of the of which cell and in cells in protein as in the and in bone maintenance of activation in this the function of in diabetes Full Text Full Text PDF PubMed Scopus (6) Google of and translational which are critical for of and of amino acids for aminoacylation of While the EPRS mutations the changes in aminoacylation kinetics and gene cell and are to the of changes to the disease on two with diabetes and bone disease as M. associated with mutations in the PubMed Scopus Google Scholar). the two patients Human an of the and the the and the and human assembly the for human ERS on synthetase the and with and the with a and a protein The between and a the of Fox J. 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