Retrograde Response to Mitochondrial Dysfunction Is Separable from TOR1/2 Regulation of Retrograde Gene Expression

Giannattasio, Sergio; Liu, Zhengchang; Thornton, Janet M.; Butow, Ronald A.

doi:10.1074/jbc.m509187200

Cited by 81 publications

(69 citation statements)

References 54 publications

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“…It is also induced in response to inhibition of amino acid biosynthetic enzymes, such as His3 and Gln1, apparently due to the central role of the tricarboxylic acid cycle in generating the carbon backbone in the biosynthesis of amino acids (44). In the present study, we have linked the RTG pathway with stationary phase mitophagy, a process that occurs under physiological conditions in an otherwise unperturbed yeast culture.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of histidine biosynthesis by the imidazoleglycerol-phosphate dehydratase (product of the HIS3 gene) inhibitor 3-AT is known to cause translocation of Rtg3 into the nucleus and transcription of RTG pathway target genes by activating the RTG signal cascade. Importantly, this signaling pathway is distinct from the GAAC and Tor signaling pathways (44), although inhibition of Tor can mimic some aspects of retrograde signaling due to mechanistic overlaps.…”

Section: Aup1 Is Required For Effective Up-regulation Of Known Rtg Pamentioning

confidence: 99%

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Aup1-mediated Regulation of Rtg3 during Mitophagy

Journo

Mor

Abeliovich

2009

Journal of Biological Chemistry

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Mitophagy is an autophagic process that degrades mitochondria by an intracellular engulfment that leads to their delivery into the lumen of the cell's hydrolytic compartment, such as the lysosome in animal cells or the vacuole in yeast. It is hypothesized that such processes serve a quality control function to prevent or slow the accumulation of malfunctioning mitochondria, which are thought in turn to underlie central aspects of the aging process in eukaryotic organisms. We recently identified a conserved mitochondrial protein phosphatase homolog, Aup1, which is required for efficient stationary phase mitophagy in yeast. In the present report, we demonstrate that the retrograde signaling pathway (RTG) is defective in aup1⌬ mutants. In agreement with a role for Aup1 in the regulation of the RTG pathway, we find that deletion of RTG3, a transcription factor that mediates the RTG response, causes a defect in stationary phase mitophagy and that deletion of AUP1 leads to changes in Rtg3 phosphorylation patterns under these conditions. In addition, we find that mitophagic conditions lead to induction of RTG pathway target genes in an Aup1-dependent fashion. Thus, our results suggest that the function of Aup1 in mitophagy could be explained through its regulation of Rtg3-dependent transcription.Mitochondria play an essential role in the physiology of eukaryotic cells. They are the sites of aerobic energy production and biosynthesis of amino acid precursors as well as nucleotide and lipid production. At the same time, mitochondria also present a threat to the cell, through production of reactive oxygen species and through the potential leakage of toxic factors, such as cytochrome c.It is generally hypothesized that quality control mechanisms scavenge malfunctioning mitochondrial compartments, safely neutralizing them before they damage cellular physiology (1, 2). One such quality control mechanism is autophagy, a catabolic process used by cells to transport cytoplasmic material for degradation in the lysosome (in animal cells) or the vacuole (in yeast, filamentous fungi, and plants) (3)(4)(5). Autophagic pathways can be classified either according to their molecular mechanism or according to their specificity. Thus, macroautophagy, the most well studied form of autophagy, is thought to be a relatively nonspecific scavenging mechanism that is induced in response to starvation cues (6 -8). Mechanistically, macroautophagy involves the generation of a cytosolic intermediate, an autophagosome, that consequently fuses with the lytic compartment or with elements of the endomembrane system that flow into the lytic compartment. On the other hand, microautophagy is a form of autophagy that involves direct involution of the vacuolar membrane, thus allowing import of material into the vacuolar lumen for degradation. There are several well documented types of selective autophagy. When Pichia pastoris is grown on methanol as a carbon source, it massively induces peroxisomes. When these cells are shifted to a better carbon source, su...

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Section: Discussionmentioning

confidence: 99%

Section: Aup1 Is Required For Effective Up-regulation Of Known Rtg Pamentioning

confidence: 99%

Aup1-mediated Regulation of Rtg3 during Mitophagy

Journo

Mor

Abeliovich

2009

Journal of Biological Chemistry

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“…Gln3-GFP and Gat1-GFP localizations respond oppositely under multiple conditions. Two aliquots of a wild type (FV063), sit4⌬ (FV066), or pph21⌬pph22⌬ (03879c) culture were transformed with pRS416-Gat1-GFP and pRS416-Gln3-GFP (42,52). Transformants were grown under identical conditions and inoculated as soon as possible into YNB-serine (Ser), glutamine (ϪGln) Ϫ, or Ϫ proline (ϪPro) medium.…”

Section: Discussionmentioning

confidence: 99%

“…The rapamycin concentration was 200 ng/ml. Strains were transformed with CEN-based plasmid pRS416-Gat1-GFP or pRS416-Gln3-GFP whose construction and detailed validation for normal regulation have appeared (42,52). Only freshly prepared transformants were assayed.…”

Section: Methodsmentioning

confidence: 99%

Distinct Phosphatase Requirements and GATA Factor Responses to Nitrogen Catabolite Repression and Rapamycin Treatment in Saccharomyces cerevisiae

Tate

Georis

Dubois

et al. 2010

Journal of Biological Chemistry

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In yeast, rapamycin (Rap)-inhibited TorC1, and the phosphatases it regulates (Sit4 and PP2A) are components of a conserved pathway regulating the response of eukaryotic cells to nutrient availability. TorC1 and intracellular nitrogen levels regulate the localization of Gln3 and Gat1, the activators of nitrogen catabolite repression (NCR)-sensitive genes whose products are required to utilize poor nitrogen sources. In nitrogen excess, Gln3 and Gat1 are cytoplasmic, and NCR-sensitive transcription is repressed. During nitrogen limitation or Rap treatment, Gln3 and Gat1 are nuclear, and transcription is derepressed. We previously demonstrated that the Sit4 and Pph21/22-Tpd3-Cdc55/Rts1 requirements for nuclear Gln3 localization differ. We now show that Sit4 and Pph21/22-Tpd3-Cdc55/Rts1 requirements for NCR-sensitive and Rap-induced nuclear Gat1 localization markedly differ from those of Gln3. Our data suggest that Gln3 and Gat1 localizations are controlled by two different regulatory pathways. Gln3 localization predominantly responds to intracellular nitrogen levels, as reflected by its stronger NCR-sensitivity, weaker response to Rap treatment, and strong response to methionine sulfoximine (Msx, a glutamine synthetase inhibitor). In contrast, Gat1 localization predominantly responds to TorC1 regulation as reflected by its weaker NCR sensitivity, stronger response to Rap, and immunity to the effects of Msx. Nuclear Gln3 localization in prolinegrown (nitrogen limited) cells exhibits no requirement for Pph21/22-Tpd3/Cdc55, whereas nuclear Gat1 localization under these conditions is absolutely dependent on Pph21/22-Tpd3/Cdc55. Furthermore, the extent to which Pph21/22-Tpd3-Cdc55 is required for the TorC1 pathway (Rap) to induce nuclear Gat1 localization is regulated in parallel with Pph21/22-Tpd3-Cdc55-dependent Gln3 dephosphorylation and NCRsensitive transcription, being highest in limiting nitrogen and lowest when nitrogen is in excess.One consequence of motif, gene, or genome duplication is the subsequent existence of multiple proteins with the same or overlapping functions. In some cases the duplicated genes evolve, acquiring easily distinguishable new functions or regulatory profiles (1-4). In others, the differences are more subtle, and a more careful study is required before they become apparent. This is the case with the Saccharomyces cerevisiae GATA family transcription factors, Gln3 and Gat1/Nil1. Both Gln3 and Gat1 are responsible for nitrogen catabolite repression (NCR) 2 -sensitive expression of genes encoding the transport and enzyme proteins needed to scavenge poor nitrogen sources (e.g. proline) when more readily usable ones are limiting or unavailable (5-8). Gln3 and Gat1 binding sites in NCR-sensitive promoters contain the core sequence GATAA that binds the well characterized zinc finger motif that defines this family of proteins (9 -11).The most apparent differences in the regulation of the GATA factors occur at the level of transcription. GAT1 expression is NCR-sensitive, Gln3-dependent, Gat1-auto-a...

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“…Total cellular RNAs were isolated using a hot phenol method as described (Giannattasio et al 2005). Cells were grown in appropriate medium to OD 600 0.6 and collected for isolation of total cellular RNA.…”

Section: Northern Blottingmentioning

confidence: 99%

TORC2 Signaling Is Antagonized by Protein Phosphatase 2A and the Far Complex in Saccharomyces cerevisiae

Pracheil

Thornton²,

Liu

2012

Genetics

Self Cite

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The target of rapamycin (TOR) kinase, a central regulator of eukaryotic cell growth, exists in two essential, yet distinct, TOR kinase complexes in the budding yeast Saccharomyces cerevisiae: rapamycin-sensitive TORC1 and rapamycin-insensitive TORC2. Lst8, a component of both TOR complexes, is essential for cell viability. However, it is unclear whether the essential function of Lst8 is linked to TORC1, TORC2, or both. To that end, we carried out a genetic screen to isolate lst8 deletion suppressor mutants. Here we report that mutations in SAC7 and FAR11 suppress lethality of lst8D and TORC2-deficient (tor2-21) mutations but not TORC1 inactivation, suggesting that the essential function of Lst8 is linked only to TORC2. More importantly, characterization of lst8D bypass mutants reveals a role for protein phosphatase 2A (PP2A) in the regulation of TORC2 signaling. We show that Far11, a member of the Far3-7-8-9-10-11 complex involved in pheromone-induced cell cycle arrest, interacts with Tpd3 and Pph21, conserved components of PP2A, and deletions of components of the Far3-7-8-9-10-11 complex and PP2A rescue growth defects in lst8D and tor2-21 mutants. In addition, loss of the regulatory B9 subunit of PP2A Rts1 or Far11 restores phosphorylation to the TORC2 substrate Slm1 in a tor2-21 mutant. Mammalian Far11 orthologs FAM40A/B exist in a complex with PP2A known as STRIPAK, suggesting a conserved functional association of PP2A and Far11. Antagonism of TORC2 signaling by PP2A-Far11 represents a novel regulatory mechanism for controlling spatial cell growth of yeast.T HE target of rapamycin (TOR) kinase is a phosphatidylinositol kinase-related protein kinase that controls eukaryotic cell growth and proliferation in response to nutrient conditions (Inoki et al. 2005;Wullschleger et al. 2006;Zoncu et al. 2011). The TOR kinase is inhibited by the complex of rapamycin and Fpr1, a peptidyl-prolyl cis-trans isomerase. The TOR kinase is conserved in eukaryotes. Unlike fungal species, which may possess two TOR kinases, higher eukaryotes such as humans possess only one. The TOR kinase exists in multi-protein complexes, which have been purified from many different eukaryotic systems. There exist two distinct TOR kinase complexes. In yeast, rapamycin-sensitive TORC1 consists of Tor1 or Tor2, Lst8, Kog1, and Tco89, and rapamycin-insensitive TORC2 consists of Tor2, Lst8, Avo1, Avo2, Avo3, and Bit61 (Loewith et al. 2002;Wedaman et al. 2003;Reinke et al. 2004). Both complexes are partially conserved in mammals: mTORC1 contains the yeast Kog1 ortholog raptor, while mTORC2 contains mSin1 and rictor, orthologs of yeast Avo1 and Avo3, respectively; GbL, the ortholog of yeast Lst8, exists in both mTORC1 and mTORC2 (Zoncu et al. 2011).TOR regulates cell growth by sensing and responding to changes in nutrient conditions (Schmelzle and Hall 2000). TORC1 has an essential function involving the regulation of cell growth that is carried out when either Tor1 or Tor2 is in the complex. Under favorable growth conditions, TORC1 promotes ce...

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Retrograde Response to Mitochondrial Dysfunction Is Separable from TOR1/2 Regulation of Retrograde Gene Expression

Cited by 81 publications

References 54 publications

Aup1-mediated Regulation of Rtg3 during Mitophagy

Aup1-mediated Regulation of Rtg3 during Mitophagy

Distinct Phosphatase Requirements and GATA Factor Responses to Nitrogen Catabolite Repression and Rapamycin Treatment in Saccharomyces cerevisiae

TORC2 Signaling Is Antagonized by Protein Phosphatase 2A and the Far Complex in Saccharomyces cerevisiae

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