Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Mol. Biol. Cell 11 (6): 2103-2115

Copyright © 2000 by The American Society for Cell Biology.

Vol. 11, Issue 6, 2103-2115, June 2000

Mitochondria-to-Nuclear Signaling Is Regulated by the Subcellular Localization of the Transcription Factors Rtg1p and Rtg3p

Takayuki Sekito, Janet Thornton, and Ronald A. Butow*

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148

Cells modulate the expression of nuclear genes in response to changes in the functional state of mitochondria, an interorganelle communication pathway called retrograde regulation. In yeast, expression of the CIT2 gene shows a typical retrograde response in that its expression is dramatically increased in cells with dysfunctional mitochondria, such as in rho o petites. Three genes control this signaling pathway: RTG1 and RTG3, which encode basic helix-loop-helix leucine zipper transcription factors that bind as heterodimer to the CIT2 upstream activation site, and RTG2, which encodes a protein of unknown function. We show that in respiratory-competent (rho +) cells in which CIT2 expression is low, Rtg1p and Rtg3p exist as a complex largely in the cytoplasm, and in rho o petites in which CIT2 expression is high, they exist as a complex predominantly localized in the nucleus. Cytoplasmic Rtg3p is multiply phosphorylated and becomes partially dephosphorylated when localized in the nucleus. Rtg2p, which is cytoplasmic in both rho + and rho o cells, is required for the dephosphorylation and nuclear localization of Rtg3p. Interaction of Rtg3p with Rtg1p is required to retain Rtg3p in the cytoplasm of rho + cells; in the absence of such interaction, nuclear localization and dephosphorylation of Rtg3p is independent of Rtg2p. Our data show that Rtg1p acts as both a positive and negative regulator of the retrograde response and that Rtg2p acts to transduce mitochondrial signals affecting the phosphorylation state and subcellular localization of Rtg3p.

* Corresponding author. E-mail address: butow{at}swmed.edu.

Molecular Biology of the Cell
Vol. 11, 2103-2115, June 2000
Copyright © 2000 by The American Society for Cell Biology

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Dysfunctional Mitochondria Modulate cAMP-PKA Signaling and Filamentous and Invasive Growth of Saccharomyces cerevisiae.
A. Aun, T. Tamm, and J. Sedman (2013)
Genetics 193, 467-481
   Abstract »    Full Text »    PDF »
The Hog1 SAPK controls the Rtg1/Rtg3 transcriptional complex activity by multiple regulatory mechanisms.
C. Ruiz-Roig, N. Noriega, A. Duch, F. Posas, and E. de Nadal (2012)
Mol. Biol. Cell 23, 4286-4296
   Abstract »    Full Text »    PDF »
Effects of Excess Succinate and Retrograde Control of Metabolite Accumulation in Yeast Tricarboxylic Cycle Mutants.
A.-P. Lin, S. L. Anderson, K. I. Minard, and L. McAlister-Henn (2011)
J. Biol. Chem. 286, 33737-33746
   Abstract »    Full Text »    PDF »
Loss of Mitochondrial DNA in the Yeast Cardiolipin Synthase crd1 Mutant Leads to Up-regulation of the Protein Kinase Swe1p That Regulates the G2/M Transition.
S. Chen, D. Liu, R. L. Finley Jr., and M. L. Greenberg (2010)
J. Biol. Chem. 285, 10397-10407
   Abstract »    Full Text »    PDF »
Aup1-mediated Regulation of Rtg3 during Mitophagy.
D. Journo, A. Mor, and H. Abeliovich (2009)
J. Biol. Chem. 284, 35885-35895
   Abstract »    Full Text »    PDF »
Mitochondrial Function Is an Inducible Determinant of Osmotic Stress Adaptation in Yeast.
M. M. Pastor, M. Proft, and A. Pascual-Ahuir (2009)
J. Biol. Chem. 284, 30307-30317
   Abstract »    Full Text »    PDF »
ISC1-dependent Metabolic Adaptation Reveals an Indispensable Role for Mitochondria in Induction of Nuclear Genes during the Diauxic Shift in Saccharomyces cerevisiae.
H. Kitagaki, L. A. Cowart, N. Matmati, D. Montefusco, J. Gandy, S. V. de Avalos, S. A. Novgorodov, J. Zheng, L. M. Obeid, and Y. A. Hannun (2009)
J. Biol. Chem. 284, 10818-10830
   Abstract »    Full Text »    PDF »
Genome Barriers between Nuclei and Mitochondria Exemplified by Cytoplasmic Male Sterility.
S. Fujii and K. Toriyama (2008)
Plant Cell Physiol. 49, 1484-1494
   Abstract »    Full Text »    PDF »
The malate-aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast.
E. Easlon, F. Tsang, C. Skinner, C. Wang, and S.-J. Lin (2008)
Genes & Dev. 22, 931-944
   Abstract »    Full Text »    PDF »
DCW11, Down-Regulated Gene 11 in CW-Type Cytoplasmic Male Sterile Rice, Encoding Mitochondrial Protein Phosphatase 2C is Related to Cytoplasmic Male Sterility.
S. Fujii and K. Toriyama (2008)
Plant Cell Physiol. 49, 633-640
   Abstract »    Full Text »    PDF »
Functional and Physical Interactions between Yeast 14-3-3 Proteins, Acetyltransferases, and Deacetylases in Response to DNA Replication Perturbations.
F. Lottersberger, A. Panza, G. Lucchini, and M. P. Longhese (2007)
Mol. Cell. Biol. 27, 3266-3281
   Abstract »    Full Text »    PDF »
Multiple Basic Helix-Loop-Helix Proteins Regulate Expression of the ENO1 Gene of Saccharomyces cerevisiae.
M. Chen and J. M. Lopes (2007)
Eukaryot. Cell 6, 786-796
   Abstract »    Full Text »    PDF »
A Fungal Family of Transcriptional Regulators: the Zinc Cluster Proteins.
S. MacPherson, M. Larochelle, and B. Turcotte (2006)
Microbiol. Mol. Biol. Rev. 70, 583-604
   Abstract »    Full Text »    PDF »
Retrograde Response to Mitochondrial Dysfunction Is Separable from TOR1/2 Regulation of Retrograde Gene Expression.
S. Giannattasio, Z. Liu, J. Thornton, and R. A. Butow (2005)
J. Biol. Chem. 280, 42528-42535
   Abstract »    Full Text »    PDF »
A Novel Degron-mediated Degradation of the RTG Pathway Regulator, Mks1p, by SCFGrr1.
Z. Liu, M. Spirek, J. Thornton, and R. A. Butow (2005)
Mol. Biol. Cell 16, 4893-4904
   Abstract »    Full Text »    PDF »
Rpm2p, a Component of Yeast Mitochondrial RNase P, Acts as a Transcriptional Activator in the Nucleus.
V. Stribinskis, H.-C. Heyman, S. R. Ellis, M. C. Steffen, and N. C. Martin (2005)
Mol. Cell. Biol. 25, 6546-6558
   Abstract »    Full Text »    PDF »
Tor Signaling and Nutrient-based Signals Converge on Mks1p Phosphorylation to Regulate Expression of Rtg1p{middle dot}Rtg3p-dependent Target Genes.
I. Dilova, S. Aronova, J. C.-Y. Chen, and T. Powers (2004)
J. Biol. Chem. 279, 46527-46535
   Abstract »    Full Text »    PDF »
Rtg2 Protein Links Metabolism and Genome Stability in Yeast Longevity.
C. Borghouts, A. Benguria, J. Wawryn, and S. M. Jazwinski (2004)
Genetics 166, 765-777
   Abstract »    Full Text »    PDF »
ATO3 Encoding a Putative Outward Ammonium Transporter Is an RTG-independent Retrograde Responsive Gene Regulated by GCN4 and the Ssy1-Ptr3-Ssy5 Amino Acid Sensor System.
N. Guaragnella and R. A. Butow (2003)
J. Biol. Chem. 278, 45882-45887
   Abstract »    Full Text »    PDF »
Tor1/2 Regulation of Retrograde Gene Expression in Saccharomyces cerevisiae Derives Indirectly as a Consequence of Alterations in Ammonia Metabolism.
J. J. Tate and T. G. Cooper (2003)
J. Biol. Chem. 278, 36924-36933
   Abstract »    Full Text »    PDF »
Longevity Regulation in Saccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin.
K. J. Bitterman, O. Medvedik, and D. A. Sinclair (2003)
Microbiol. Mol. Biol. Rev. 67, 376-399
   Abstract »    Full Text »    PDF »
Response of Genes Associated with Mitochondrial Function to Mild Heat Stress in Yeast Saccharomyces cerevisiae.
K. Sakaki, K. Tashiro, S. Kuhara, and K. Mihara (2003)
J. Biochem. 134, 373-384
   Abstract »    Full Text »    PDF »
Mitochondria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae.
A. K. Rasmussen, A. Chatterjee, L. J. Rasmussen, and K. K. Singh (2003)
Nucleic Acids Res. 31, 3909-3917
   Abstract »    Full Text »    PDF »
Tor Kinases Are in Distinct Membrane-associated Protein Complexes in Saccharomyces cerevisiae.
K. P. Wedaman, A. Reinke, S. Anderson, J. Yates III, J. M. McCaffery, and T. Powers (2003)
Mol. Biol. Cell 14, 1204-1220
   Abstract »    Full Text »    PDF »
Identification of RTG2 as a Modifier Gene for CTG{middle dot}CAG Repeat Instability in Saccharomyces cerevisiae.
S. Bhattacharyya, M. L. Rolfsmeier, M. J. Dixon, K. Wagoner, and R. S. Lahue (2002)
Genetics 162, 579-589
   Abstract »    Full Text »    PDF »
Mitochondrial Development during Life Cycle Differentiation of African Trypanosomes: Evidence for a Kinetoplast-dependent Differentiation Control Point.
M. W. Timms, F. J. van Deursen, E. F. Hendriks, and K. R. Matthews (2002)
Mol. Biol. Cell 13, 3747-3759
   Abstract »    Full Text »    PDF »
Cytoplasmic Compartmentation of Gln3 during Nitrogen Catabolite Repression and the Mechanism of Its Nuclear Localization during Carbon Starvation in Saccharomyces cerevisiae.
K. H. Cox, J. J. Tate, and T. G. Cooper (2002)
J. Biol. Chem. 277, 37559-37566
   Abstract »    Full Text »    PDF »
Mks1p Is Required for Negative Regulation of Retrograde Gene Expression in Saccharomyces cerevisiae but Does Not Affect Nitrogen Catabolite Repression-sensitive Gene Expression.
J. J. Tate, K. H. Cox, R. Rai, and T. G. Cooper (2002)
J. Biol. Chem. 277, 20477-20482
   Abstract »    Full Text »    PDF »
The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine.
J. L. Crespo, T. Powers, B. Fowler, and M. N. Hall (2002)
PNAS 99, 6784-6789
   Abstract »    Full Text »    PDF »
A novel Rtg2p activity regulates nitrogen catabolism in yeast.
M. M. Pierce, M.-L. Maddelein, B. T. Roberts, and R. B. Wickner (2001)
PNAS 98, 13213-13218
   Abstract »    Full Text »    PDF »
Regulation of Physiological Rates in Caenorhabditis elegans by a tRNA-Modifying Enzyme in the Mitochondria.
J. Lemieux, B. Lakowski, A. Webb, Y. Meng, A. Ubach, F. Bussiere, T. Barnes, and S. Hekimi (2001)
Genetics 159, 147-157
   Abstract »    Full Text »    PDF »
Genome-wide Responses to Mitochondrial Dysfunction.
C. B. Epstein, J. A. Waddle, W. Hale IV, V. Dave, J. Thornton, T. L. Macatee, H. R. Garner, and R. A. Butow (2001)
Mol. Biol. Cell 12, 297-308
   Abstract »    Full Text »
Copper-Modulated Gene Expression and Senescence in the Filamentous Fungus Podospora anserina.
C. Borghouts, A. Werner, T. Elthon, and H. D. Osiewacz (2001)
Mol. Cell. Biol. 21, 390-399
   Abstract »    Full Text »    PDF »
Mechanism of Metabolic Control: Target of Rapamycin Signaling Links Nitrogen Quality to the Activity of the Rtg1 and Rtg3 Transcription Factors.
A. Komeili, K. P. Wedaman, E. K. O'Shea, and T. Powers (2000)
J. Cell Biol. 151, 863-878
   Abstract »    Full Text »    PDF »
Interorganellar Communication. ALTERED NUCLEAR GENE EXPRESSION PROFILES IN A YEAST MITOCHONDRIAL DNA MUTANT.
A. Traven, J. M. S. Wong, D. Xu, M. Sopta, and C. J. Ingles (2001)
J. Biol. Chem. 276, 4020-4027
   Abstract »    Full Text »    PDF »
A novel Rtg2p activity regulates nitrogen catabolism in yeast.
M. M. Pierce, M.-L. Maddelein, B. T. Roberts, and R. B. Wickner (2001)
PNAS 98, 13213-13218
   Abstract »    Full Text »    PDF »
RTG-dependent Mitochondria-to-Nucleus Signaling Is Regulated by MKS1 and Is Linked to Formation of Yeast Prion [URE3].
T. Sekito, Z. Liu, J. Thornton, and R. A. Butow (2002)
Mol. Biol. Cell 13, 795-804
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882