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Gene Review

CIT2  -  citrate (Si)-synthase CIT2

Saccharomyces cerevisiae S288c

Synonyms: Citrate synthase, peroxisomal, YCR005C, YCR043, YCR5C
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Disease relevance of CIT2

  • The amino terminus of the CIT2 primary translation product extends 20 residues beyond the amino termini of the E. coli and porcine enzymes [1].

High impact information on CIT2

  • RTG1 encodes a protein of 177 amino acids with similarity to basic helix-loop-helix transcription factors that likely functions at the CIT2 UASr [2].
  • Here we show that retrograde regulation of the yeast CIT2 gene encoding peroxisomal citrate synthase depends on a new class of upstream activation site element (UASr) and two previously unidentified genes, RTG1 and RTG2 [2].
  • In addition, we have demonstrated that the carboxy-terminal seven amino acids of citrate synthase of Saccharomyces cerevisiae encoded by CIT2 and containing the canonical -SKL represents a targeting signal sufficient to direct reporter proteins to peroxisomes [3].
  • We have previously shown that the RTG genes control the retrograde pathway, defined as a change in the expression of a subset of nuclear genes, e.g., the glyoxylate cycle CIT2 gene, in response to changes in the functional state of mitochondria [4].
  • Here, we describe the cloning and characterization of RTG3, a gene encoding a 54-kDa bHLH/Zip protein that is also required for CIT2 expression [5].

Biological context of CIT2

  • Different blocks in the tricarboxylic acid cycle also elicit an increase in CIT2 expression, but not to the extent observed in petites [6].
  • To analyze the function of the N-terminal region of Cit2p in protein trafficking, we constructed the N-terminal domain-swapped versions of Cit1p and Cit2p [7].
  • We demonstrate that both of the Rtg1p-Rtg3p binding sites in the UAS(r) element are required in vivo and act synergistically for CIT2 expression [5].
  • Cells that lack their mitochondrial genome (rho0 cells) trigger expression of the nuclear CIT2 gene in order to ensure adequate amino acid biosynthesis [8].
  • The DNA sequence of CIT2 presented provides a possible explanation for why the CIT2 product, unlike the CIT1 product, fails to be imported into mitochondria [1].

Anatomical context of CIT2

  • These data indicate that, in addition to their role in retrograde regulation of CIT2, the RTG genes are important for expression of genes encoding peroxisomal proteins and are thus key components in a novel, three-way path of communication between mitochondria, the nucleus, and peroxisomes [6].
  • The possible role of this sequence in targeting this CIT2 product to a nonmitochondrial organelle is discussed [1].

Associations of CIT2 with chemical compounds

  • Genes CIT1 and CIT2 from Saccharomyces cerevisiae encode mitochondrial and peroxisomal citrate synthases involved in the Krebs tricarboxylic acid (TCA) cycle and glyoxylate pathway, respectively [9].
  • Both fusions, Cit1::Cit2 and Cit2::Cit1, complemented the glutamate auxotrophy caused by the double-disruption of the CIT1 and CIT2 genes [7].
  • Rtg3p and Rtg1p are basic helix-loop-helix/leucine zipper protein transcription factors in yeast that interact and bind to sites in an upstream activation sequence element in the 5'-flanking region of CIT2, a gene encoding a peroxisomal isoform of citrate synthase [10].
  • Because this prediction did not accommodate earlier observations that CIT2 (a retrograde gene) expression is higher in glutamine than proline containing medium, we investigated retrograde regulation further [11].
  • Here is shown that the lack of urmylation causes derepression of the GAP1 gene (encoding a nitrogen-regulated broad-spectrum amino acid-scavenging permease) in the presence of rich nitrogen sources, and simultaneous inhibition of the expression of CIT2, a TCA-cycle gene involved in the production of glutamate and glutamine [12].

Regulatory relationships of CIT2

  • Rtg1p is a basic helix-loop-helix transcription factor in the yeast Saccharomyces cerevisiae that is required for basal and regulated expression of CIT2, the gene encoding a peroxisomal isoform of citrate synthase [13].

Other interactions of CIT2

  • Previous studies identified a basic helix-loop-helix-leucine zipper (bHLH/Zip) transcription factor encoded by the RTG1 gene that is required for both basal expression of the CIT2 gene and its increased expression in respiratory-deficient cells [5].
  • The double yfh1 ras2 mutant has increased mRNA levels of CIT2 gene and augmented catalase activity [14].
  • Our results also indicate the effects of rapamycin treatment on CIT2 transcription, and hence Tor1/2 regulation of retrograde gene expression occur indirectly as a consequence of alterations in ammonia and glutamate metabolism [11].
  • To investigate the connections between these two signaling pathways, we have analyzed rapamycin sensitivity of the expression of the RTG target gene CIT2 and of two NCR-sensitive genes, GLN1 and DAL5, in respiratory-competent (rho+) and -incompetent (rho0) yeast cells [15].


  1. Mitochondrial and nonmitochondrial citrate synthases in Saccharomyces cerevisiae are encoded by distinct homologous genes. Rosenkrantz, M., Alam, T., Kim, K.S., Clark, B.J., Srere, P.A., Guarente, L.P. Mol. Cell. Biol. (1986) [Pubmed]
  2. RTG1 and RTG2: two yeast genes required for a novel path of communication from mitochondria to the nucleus. Liao, X., Butow, R.A. Cell (1993) [Pubmed]
  3. Two independent peroxisomal targeting signals in catalase A of Saccharomyces cerevisiae. Kragler, F., Langeder, A., Raupachova, J., Binder, M., Hartig, A. J. Cell Biol. (1993) [Pubmed]
  4. A transcriptional switch in the expression of yeast tricarboxylic acid cycle genes in response to a reduction or loss of respiratory function. Liu, Z., Butow, R.A. Mol. Cell. Biol. (1999) [Pubmed]
  5. A basic helix-loop-helix-leucine zipper transcription complex in yeast functions in a signaling pathway from mitochondria to the nucleus. Jia, Y., Rothermel, B., Thornton, J., Butow, R.A. Mol. Cell. Biol. (1997) [Pubmed]
  6. RTG genes in yeast that function in communication between mitochondria and the nucleus are also required for expression of genes encoding peroxisomal proteins. Chelstowska, A., Butow, R.A. J. Biol. Chem. (1995) [Pubmed]
  7. Identification of a cryptic N-terminal signal in Saccharomyces cerevisiae peroxisomal citrate synthase that functions in both peroxisomal and mitochondrial targeting. Lee, J.G., Cho, S.P., Lee, H.S., Lee, C.H., Bae, K.S., Maeng, P.J. J. Biochem. (2000) [Pubmed]
  8. Retrograde regulation of multidrug resistance in Saccharomyces cerevisiae. Moye-Rowley, W.S. Gene (2005) [Pubmed]
  9. Metabolic effects of mislocalized mitochondrial and peroxisomal citrate synthases in yeast Saccharomyces cerevisiae. Vélot, C., Lebreton, S., Morgunov, I., Usher, K.C., Srere, P.A. Biochemistry (1999) [Pubmed]
  10. Rtg3p, a basic helix-loop-helix/leucine zipper protein that functions in mitochondrial-induced changes in gene expression, contains independent activation domains. Rothermel, B.A., Thornton, J.L., Butow, R.A. J. Biol. Chem. (1997) [Pubmed]
  11. Tor1/2 regulation of retrograde gene expression in Saccharomyces cerevisiae derives indirectly as a consequence of alterations in ammonia metabolism. Tate, J.J., Cooper, T.G. J. Biol. Chem. (2003) [Pubmed]
  12. Urmylation controls Nil1p and Gln3p-dependent expression of nitrogen-catabolite repressed genes in Saccharomyces cerevisiae. Rubio-Texeira, M. FEBS Lett. (2007) [Pubmed]
  13. Transactivation by Rtg1p, a basic helix-loop-helix protein that functions in communication between mitochondria and the nucleus in yeast. Rothermel, B.A., Shyjan, A.W., Etheredge, J.L., Butow, R.A. J. Biol. Chem. (1995) [Pubmed]
  14. Iron toxicity protection by truncated Ras2 GTPase in yeast strain lacking frataxin. Kucej, M., Foury, F. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  15. Retrograde response to mitochondrial dysfunction is separable from TOR1/2 regulation of retrograde gene expression. Giannattasio, S., Liu, Z., Thornton, J., Butow, R.A. J. Biol. Chem. (2005) [Pubmed]
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