10 research outputs found
Plasma membrane proteins Slm1 and Slm2 mediate activation of the AGC kinase Ypk1 by TORC2 and sphingolipids in S. cerevisiae
TOR Complex 2-Ypk1 Signaling Maintains Sphingolipid Homeostasis by Sensing and Regulating ROS Accumulation
Reactive oxygen species (ROS) are produced during normal metabolism and can function as signaling molecules. However, ROS at elevated levels can damage cells. Here, we identify the conserved target of rapamycin complex 2 (TORC2)/Ypk1 signaling module as an important regulator of ROS in the model eukaryotic organism, S. cerevisiae. We show that TORC2/Ypk1 suppresses ROS produced both by mitochondria as well as by nonmitochondrial sources, including changes in acidification of the vacuole. Furthermore, we link vacuole-related ROS to sphingolipids, essential components of cellular membranes, whose synthesis is also controlled by TORC2/Ypk1 signaling. In total, our data reveal that TORC2/Ypk1 act within a homeostatic feedback loop to maintain sphingolipid levels and that ROS are a critical regulatory signal within this system. Thus, ROS sensing and signaling by TORC2/Ypk1 play a central physiological role in sphingolipid biosynthesis and in the maintenance of cell growth and viability
Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in <i>Saccharomyces cerevisiae</i>
The target of rapamycin (TOR) is a critical regulator
of growth,
survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin
has been used extensively to elucidate the TOR related signal pathway
but is limited by its inability to inhibit TORC2. We used an unbiased
cell proliferation assay of a kinase inhibitor library to discover
QL-IX-55 as a potent inhibitor of S. <i>cerevisiae</i> growth.
The functional target of QL-IX-55 is the ATP-binding site of TOR2
as evidenced by the discovery of resistant alleles of TOR2 through
rational design and unbiased selection strategies. QL-IX-55 is capable
of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2)
as demonstrated by biochemical IP kinase assays (IC<sub>50</sub> <50
nM) and cellular assays for inhibition of substrate YPK1 phosphorylation.
In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent
transcription, which suggests that this compound will be a powerful
probe to dissect the Tor2/TORC2-related signaling pathway in yeast
Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in <i>Saccharomyces cerevisiae</i>
The target of rapamycin (TOR) is a critical regulator
of growth,
survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin
has been used extensively to elucidate the TOR related signal pathway
but is limited by its inability to inhibit TORC2. We used an unbiased
cell proliferation assay of a kinase inhibitor library to discover
QL-IX-55 as a potent inhibitor of S. <i>cerevisiae</i> growth.
The functional target of QL-IX-55 is the ATP-binding site of TOR2
as evidenced by the discovery of resistant alleles of TOR2 through
rational design and unbiased selection strategies. QL-IX-55 is capable
of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2)
as demonstrated by biochemical IP kinase assays (IC<sub>50</sub> <50
nM) and cellular assays for inhibition of substrate YPK1 phosphorylation.
In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent
transcription, which suggests that this compound will be a powerful
probe to dissect the Tor2/TORC2-related signaling pathway in yeast
Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in Saccharomyces cerevisiae
The target of rapamycin (TOR) is a critical regulator of growth, survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin has been used extensively to elucidate the TOR related signal pathway but is limited by its inability to inhibit TORC2. We used an unbiased cell proliferation assay of a kinase inhibitor library to discover QL-IX-55 as a potent inhibitor of S. cerevisiae growth. The functional target of QL-IX-55 is the ATP-binding site of TOR2 as evidenced by the discovery of resistant alleles of TOR2 through rational design and unbiased selection strategies. QL-IX-55 is capable of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2) as demonstrated by biochemical IP kinase assays (IC(50) >50 nM) and cellular assays for inhibition of substrate YPK1 phosphorylation. In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent transcription, which suggests that this compound will be a powerful probe to dissect the Tor2/TORC2-related signaling pathway in yeast
Geochemistry of Carbonates on Mars: Implications for Climate History and Nature of Aqueous Environments
The impact of treatment with avacopan on health-related quality of life in antineutrophil cytoplasmic antibody-associated vasculitis: a post-hoc analysis of data from the ADVOCATE trial
Isotope ratios of H, C, and O in CO2 and H2O of the Martian atmosphere
Stable isotope ratios of H, C, and O are powerful indicators of a wide variety of planetary geophysical processes, and for Mars they reveal the record of loss of its atmosphere and subsequent interactions with its surface such as carbonate formation. We report in situ measurements of the isotopic ratios of D/H and O-18/O-16 in water and C-13/C-12, O-18/O-16, O-17/O-16, and (CO)-C-13-O-18/(CO)-C-12-O-16 in carbon dioxide, made in the martian atmosphere at Gale Crater from the Curiosity rover using the Sample Analysis at Mars (SAM)'s tunable laser spectrometer (TLS). Comparison between our measurements in the modern atmosphere and those of martian meteorites such as ALH 84001 implies that the martian reservoirs of CO2 and H2O were largely established similar to 4 billion years ago, but that atmospheric loss or surface interaction may be still ongoing