Homeostasis of branched-chain amino acids is critical for the activity of TOR signaling in Arabidopsis

Cao, Pengfei; Kim, Sang-Jin; Xing, Anqi; Schenck, Craig A.; Liu, Lu; Jiang, Nan; Wang, Jie; Brandizzí, Federica

doi:10.7554/elife.50747

Cited by 83 publications

(109 citation statements)

References 86 publications

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“…In mammals and yeast, the RAPTOR-independent TORC2 complex regulates actin filamentation through multiple pathways ( Jacinto et al, 2004 ; Loewith et al, 2002 ; Rispal et al, 2015 ; Sarbassov and Kim, 2004 ; Schmidt et al, 1996 ). Recently, a forward genetic screen in Arabidopsis found that a recessive allele of isopropylmalate synthase 1 ( IPMS1 ) promotes actin filamentation in a TOR-dependent pathway ( Cao et al, 2019 ). IPMS1 is the first committed step of leucine biosynthesis; accordingly, ipms1 mutants exhibit broad defects in free amino acid accumulation ( Cao et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Scarpin

Leiboff

Brunkard

2020

eLife

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TARGET OF RAPAMYCIN (TOR) is a protein kinase that coordinates eukaryotic metabolism. In mammals, TOR specifically promotes translation of ribosomal protein mRNAs when amino acids are available to support protein synthesis. The mechanisms controlling translation downstream from TOR remain contested, however, and are largely unexplored in plants. To define these mechanisms in plants, we globally profiled the plant TOR-regulated transcriptome, translatome, proteome, and phosphoproteome. We found that TOR regulates ribosome biogenesis in plants at multiple levels, but through mechanisms that do not directly depend on 5′ oligopyrimidine tract motifs (5′TOPs) found in mammalian ribosomal protein mRNAs. We then show that the TOR-LARP1-5′TOP signaling axis is conserved in plants and regulates expression of a core set of eukaryotic 5′TOP mRNAs, as well as new, plant-specific 5′TOP mRNAs. Our study illuminates ancestral roles of the TOR-LARP1-5′TOP metabolic regulatory network and provides evolutionary context for ongoing debates about the molecular function of LARP1.

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Section: Resultsmentioning

confidence: 99%

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Scarpin

Leiboff

Brunkard

2020

eLife

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“…The ETF/ETFQO pathway has been shown to contribute significant amounts of electrons in stress situations (Ishizaki et al, 2005; Pires et al, 2016). The concomitant increase in BCKAs and particularly BCAAs may contribute to the dwarf phenotype as disruption in BCAA homeostasis has been shown to lead to pleiotropic effects including growth retardation (Cao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Branched-chain amino acid catabolism depends on GRXS15 through mitochondrial lipoyl cofactor homeostasis

Moseler

Kruse

et al. 2020

Preprint

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Iron-sulfur (Fe-S) clusters are ubiquitous cofactors in all life and are used in a wide array of diverse biological processes, including electron transfer chains and several metabolic pathways. Biosynthesis machineries for Fe-S clusters exist in plastids, the cytosol and mitochondria. A single monothiol glutaredoxin (GRX) has been shown to be involved in Fe-S cluster assembly in mitochondria of yeast and mammals. In plants, the role of the mitochondrial homologue GRXS15 has only partially been characterized. Arabidopsis grxs15 null mutants are not viable, but mutants complemented with the variant GRXS15 K83A develop with a dwarf phenotype. In an in-depth metabolic analysis, we show that most Fe-S cluster-dependent processes are not affected, including biotin biosynthesis, molybdenum cofactor biosynthesis and the electron transport chain. Instead, we observed an increase in most TCA cycle intermediates and amino acids, especially pyruvate, 2-oxoglutarate, glycine and branched-chain amino acids (BCAAs). The most pronounced accumulation occurred in branched-chain α-keto acids (BCKAs), the first degradation products resulting from deamination of BCAAs. In wild-type plants, pyruvate, 2-oxoglutarate, glycine and BCKAs are all metabolized through decarboxylation by four mitochondrial lipoyl cofactor-dependent dehydrogenase complexes. Because these enzyme complexes are very abundant and the biosynthesis of the lipoyl cofactor depends on continuous Fe-S cluster supply to lipoyl synthase, this could explain why lipoyl cofactor-dependent processes are most sensitive to restricted Fe-S supply in GRXS15 K83A mutants.One-sentence summaryDeficiency in GRXS15 restricts protein lipoylation and causes metabolic defects in lipoyl cofactor-dependent dehydrogenase complexes, with branched-chain amino acid catabolism as dominant bottleneck.

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“…In mammals and yeast, the RAPTOR-independent TORC2 complex regulates actin filamentation through multiple pathways (Dos et al, 2004;Jacinto et al, 2004;Loewith et al, 2002;Rispal et al, 2015;Schmidt et al, 1996). Recently, a forward genetic screen in Arabidopsis found that a recessive allele of ISOPROPYLMALATE SYNTHASE 1 (IPMS1) promotes actin filamentation in a TORdependent pathway (Cao et al, 2019). IPMS1 is the first committed step of leucine biosynthesis; accordingly, ipms1 mutants exhibit broad defects in free amino acid accumulation (Cao et al, 2019).…”

Section: The Seedling Tor-regulated Proteome and Phosphoproteomementioning

confidence: 99%

“…Recently, a forward genetic screen in Arabidopsis found that a recessive allele of ISOPROPYLMALATE SYNTHASE 1 (IPMS1) promotes actin filamentation in a TORdependent pathway (Cao et al, 2019). IPMS1 is the first committed step of leucine biosynthesis; accordingly, ipms1 mutants exhibit broad defects in free amino acid accumulation (Cao et al, 2019). While the exact cause remains undefined, the disruption of amino acid metabolism in ipms1 mutants apparently increases cellular TOR activity (Cao et al, 2019;Schaufelberger et al, 2019).…”

Section: The Seedling Tor-regulated Proteome and Phosphoproteomementioning

confidence: 99%

“…ACTIN DEPOLYMERIZING FACTOR 11 (ADF11), part of the cofilin family of actin destabilizing proteins, is also encoded by a 5′TOP mRNA, providing another possible connection between TOR and actin filamentation (Bernstein and Bamburg, 2010). These pathways can be further interrogated by determining their contribution to cytoskeleton defects in mutants with hyperactive TOR activity, such as ipms1 (Cao et al, 2019).…”

Section: Metabolic Control Of Cytoskeletal Dynamics By Tor: Possible mentioning

confidence: 99%

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Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in protein translation

Scarpin

Leiboff

Brunkard

2020

Preprint

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Author ContributionsAll authors contributed to the design, execution, and analysis of experiments. S.L. specifically contributed to the design and computational analysis of RNA sequencing experiments. M.R.S. and J.O.B. wrote the manuscript. ABSTRACTTARGET OF RAPAMYCIN (TOR) is a deeply conserved protein kinase that coordinates eukaryotic metabolism with nutrient availability. In mammals, TOR specifically promotes translation of ribosomal protein mRNAs when amino acids are available to support protein synthesis.The mechanisms controlling translation downstream from TOR remain contested, however, and are largely unexplored in plants.Here, we took parallel global profiling approaches to define the in planta TOR-regulated transcriptome, translatome, proteome, and phosphoproteome. We found that TOR regulates ribosome biogenesis in plants at multiple levels, but through mechanisms that do not directly depend on the canonical 5′ oligopyrimidine tract motif (5′TOP) found in mammalian ribosomal protein mRNAs. To investigate this further, we focused on a putative TOR substrate identified in our phosphoproteome: LARP1, a eukaryotic RNAbinding protein that is proposed to mediate TOR translational control of 5′TOP mRNAs in humans and that has gained increased interest because it associates with SARS-CoV-2. By conducting parallel global profiling experiments with larp1 mutants, we discovered that the TOR-LARP1 signaling axis controls 5′TOP mRNA translation in plants and defined a set of conserved eukaryotic 5′TOP mRNAs that encode cyclins, importins/karyopherins, translation elongation factors, and TCTP1, among others. We then identified novel, plantspecific 5′TOP mRNAs involved in critical biological processes, including ribosome biogenesis, chromatin remodeling, and auxin signaling. Our study illuminates the ancestral roles of the TOR-LARP1-5′TOP metabolic regulatory network and provides evolutionary context for ongoing debates about the molecular function of LARP1 in eukaryotic cells.

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Homeostasis of branched-chain amino acids is critical for the activity of TOR signaling in Arabidopsis

Cited by 83 publications

References 86 publications

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Branched-chain amino acid catabolism depends on GRXS15 through mitochondrial lipoyl cofactor homeostasis

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in protein translation

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