TOR regulates late steps of ribosome maturation in the nucleoplasm via Nog1 in response to nutrients

Honma, Yoshimi; Kitamura, Aiko; Shioda, Ryo; Maruyama, Hironori; Ozaki, Kanako; Oda, Yoko; Mini, Thierry; Jenö, Paul; Maki, Yoshitaka; Yonezawa, Kazuyoshi; Hurt, Ed; Ueno, Masaru; Uritani, Masahiro; Hall, Michael N.; Ushimaru, Takashi

doi:10.1038/sj.emboj.7601262

Cited by 60 publications

(59 citation statements)

References 62 publications

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“…We demonstrated that TORC1 basic functions are conserved in T brucei. Cells with reduced levels of TbTOR1 showed disperse nucleolar localization of RNA pol I, protein synthesis inhibition, and reduced cell size, as previously shown for other eukaryotes (22)(23)(24).…”

Section: Discussionmentioning

confidence: 51%

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation

Barquilla

Crespo

Navarro

2008

Proc. Natl. Acad. Sci. U.S.A.

121

153

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Target of rapamycin (TOR) kinases control cell growth through two functionally distinct multiprotein complexes. TOR complex 1 (TORC1) controls temporal cell growth and is sensitive to rapamycin, whereas TOR complex 2 (TORC2) is rapamycin resistant and regulates spatial cell growth. Here, we identified two TOR orthologues, TbTOR1 and TbTOR2, in the protozoan parasite Trypanosoma brucei, as well as orthologues of the well-known TORC1 and TORC2 partners, KOG1/raptor and AVO3/rictor. TbTOR proteins differ in their functions, subcellular localization, and rapamycin sensitivity. TbTOR1 controls cell growth by regulating cell cycle, nucleolus structure, and protein synthesis, whereas TbTOR2 coordinates cell polarization and cytokinesis. Rapamycin treatment of bloodstream trypanosomes resulted in a pronounced reduction of cell proliferation, with an EC 50 of 152 nM. Unique for a eukaryote, we observed that rapamycin acted exclusively by preventing TORC2 formation, with no effect on TORC1. Our findings on TOR signaling in this protozoan, which is located in a distal position in the eukaryotic cell lineage, highlight the clinical possibilities of rapamycin derivates and provide valuable insights into understanding rapamycin-mediated inhibition of TORC2.FKBP12 ͉ PIKK ͉ target of rapamycin ͉ Trypanosoma brucei

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Section: Discussionmentioning

confidence: 51%

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation

Barquilla

Crespo

Navarro

2008

Proc. Natl. Acad. Sci. U.S.A.

121

153

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“…The finding that TOR signaling affects yeast Nog1p and Nog2p suggests a similar link may exist between TOR signaling and Drosophila NS1. Conversely, inactivation of TOR kinase did not enhance nucleolar retention of the permuted GTPase Nug1p, or that of Bsm1, the nuclear and nucleolar factor required for 40S subunit assembly (Honma et al, 2006). Our future efforts will test the hypothesis that TOR signaling regulates ribosome biosynthesis and/or nuclear export by modulating NS1 activity either directly or indirectly.…”

Section: Possible Links Between Nucleostemin and Stress Responsementioning

confidence: 99%

“…A block in TOR signaling by either nutrient starvation or rapamycin treatment entrapped Nog1p and its associated proteins within nucleoli. Honma et al (2006) concluded that TOR signaling is necessary for the release of the Nog1p complex from the nucleolus perhaps after participating in a relatively early step in 60S subunit assembly. Interestingly, another yeast nuclear and nucleolar GTPase, Nog2p, also accumulated within nucleoli when TOR was inactivated, thus supporting the notion that activated TOR kinase regulates ribosome maturation and export.…”

Section: Possible Links Between Nucleostemin and Stress Responsementioning

confidence: 99%

“…Specifically, a link between TOR signaling and large ribosomal subunit maturation and export has been established with Nog1p, a GTPase in Saccharomyces cerevisiae that shuttles between the nucleolus and nucleoplasm (Honma et al, 2006). Nog1p is essential for both early and late-stage 60S ribosomal subunit biosynthesis.…”

Section: Possible Links Between Nucleostemin and Stress Responsementioning

confidence: 99%

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Knockdown of theDrosophilaGTPase Nucleostemin 1 Impairs Large Ribosomal Subunit Biogenesis, Cell Growth, and Midgut Precursor Cell Maintenance

Rosby

Cui

Rogers

et al. 2009

MBoC

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Mammalian nucleostemin (NS) is a nucleolar guanosine triphosphate-binding protein implicated in cell cycle progression, stem cell proliferation, and ribosome assembly. Drosophila melanogaster contains a four-member nucleostemin family (NS1-4). NS1 is the closest orthologue to human NS; it shares 33% identity and 67% similarity with human NS. We show that NS1 has intrinsic GTPase and ATPase activity and that it is present within nucleoli of most larval and adult cells. Endogenous NS1 and lightly expressed green fluorescent protein (GFP)-NS1 enrich within the nucleolar granular regions as expected, whereas overexpressed GFP-NS1 localized throughout the nucleolus and nucleoplasm, and to several transcriptionally active interbands of polytene chromosomes. Severe overexpression correlated with the appearance of melanotic tumors and larval/pupal lethality. Depletion of 60% of NS1 transcripts also lead to larval and pupal lethality. NS1 protein depletion correlated with the loss of imaginal island (precursor) cells in the larval midgut and to an apparent block in the nucleolar release of large ribosomal subunits in terminally differentiated larval midgut polyploid cells. Ultrastructural examination of larval Malpighian tubule cells depleted for NS1 showed a loss of cytoplasmic ribosomes and a concomitant appearance of cytoplasmic preautophagosomes and lysosomes. We interpret the appearance of these structures as indicators of cell stress response. INTRODUCTIONMammalian nucleostemin (NS) is a nucleolar guanosine triphosphate (GTP)-binding protein first characterized in embryonic and neuronal stem cells and in certain cancer cells where it probably plays regulatory roles in cell cycle progression and ribosome biogenesis McKay, 2002, 2005; reviewed by Ma and Pederson, 2008b). Steadystate concentrations of NS drop to undetectable levels just before rat cortical stem cell differentiation (Tsai and McKay, 2002), suggesting that reduced expression of NS regulates stem cell proliferation and differentiation by triggering exit from the cell cycle (Normile, 2002;Tsai and McKay, 2002;Beekman et al., 2006). Mammalian NS rapidly cycles between the nucleolus and the nucleoplasm. Retention of NS within the nucleolus is prolonged when it binds GTP (Misteli, 2005;Tsai and McKay, 2005;Meng et al., 2006Meng et al., , 2007. GTP bound to the central region of NS is thought to stabilize interactions between its amino-terminal basic domain and other nucleolar components, whereas NS redistributes to the nucleoplasm when GTP binding is impaired by mutation (Tsai and McKay, 2005). Coimmunoprecipitation, yeast twohybrid, and bimolecular fluorescence complementation assays demonstrated an interaction between NS and nucleophosmin (B23) (Ma and Pederson, 2008a), a multifunctional chaperone that probably participates in the later stages of ribosome assembly within the granular component of nucleoli. Similar to NS, nucleophosmin probably plays a role in cell proliferation (Szebeni et al., 2003;Grisendi et al., 2006). Recent studies suggest that NS ...

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“…For example, the nop7-1 mutation is synthetically lethal with specific mutant alleles of DRS1, a putative DEAD box helicase necessary for 60S subunit assembly (Adams et al, 2002), and overexpression of DRS1 suppresses certain nop7 mutants (L. Tang, unpublished data). Overexpression of NOP7 suppresses the thermosensitive growth defects of certain mutations in ribosome assembly factor Nog1 (Honma et al, 2006). More experiments need to be done to discover proteins that physically associate with the Nop7-subcomplex within nascent ribosomes.…”

Section: Roles For Domains Other Than Interactions Within the Nop7-sumentioning

confidence: 99%

Interactions among Ytm1, Erb1, and Nop7 Required for Assembly of the Nop7-Subcomplex in Yeast Preribosomes

Tang

Sahasranaman

Jakovljevic

et al. 2008

MBoC

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In Saccharomyces cerevisiae, more than 180 assembly factors associate with preribosomes to enable folding of pre-rRNA, recruitment of ribosomal proteins, and processing of pre-rRNAs to produce mature ribosomes. To examine the molecular architecture of preribosomes and to connect this structure to functions of each assembly factor, assembly subcomplexes have been purified from preribosomal particles. The Nop7-subcomplex contains three assembly factors: Nop7, Erb1, and Ytm1, each of which is necessary for conversion of 27SA 3 pre-rRNA to 27SB S pre-rRNA. However, interactions among these three proteins and mechanisms of their recruitment and function in pre-rRNPs are poorly understood. Here we show that Ytm1, Erb1, and Nop7 assemble into preribosomes in an interdependent manner. We identified which domains within Ytm1, Erb1, and Nop7 are necessary for their interaction with each other and are sufficient for recruitment of each protein into preribosomes. Dominant negative effects on growth and ribosome biogenesis caused by overexpressing truncated Ytm1, Erb1, or Nop7 constructs, and recessive phenotypes of the truncated proteins revealed not only interaction domains but also other domains potentially important for each protein to function in ribosome biogenesis. Our data suggest a model for the architecture of the Nop7-subcomplex and provide potential functions of domains of each protein.

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TOR regulates late steps of ribosome maturation in the nucleoplasm via Nog1 in response to nutrients

Cited by 60 publications

References 62 publications

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation

Knockdown of theDrosophilaGTPase Nucleostemin 1 Impairs Large Ribosomal Subunit Biogenesis, Cell Growth, and Midgut Precursor Cell Maintenance

Interactions among Ytm1, Erb1, and Nop7 Required for Assembly of the Nop7-Subcomplex in Yeast Preribosomes

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