The target of rapamycin complex 1 (TORC1) is an evolutionarily conserved sensor of nutrient availability. Genetic and pharmacological studies in the yeast Saccharomyces cerevisiae have provided mechanistic insights on the regulation of TORC1 signaling in response to nutrients. Using a highly specific antibody that recognizes phosphorylation of the bona fide TORC1 target ribosomal protein S6 (Rps6) in yeast, we found that nutrients rapidly induce Rps6 phosphorylation in a TORC1-dependent manner. Moreover, we demonstrate that Ypk3, an AGC kinase which exhibits high homology to human S6 kinase (S6K), is required for the phosphorylation of Rps6 in vivo. Rps6 phosphorylation is completely abolished in cells lacking Ypk3 (ypk3Δ), whereas Sch9, previously reported to be the yeast ortholog of S6K, is dispensable for Rps6 phosphorylation. Phosphorylation-deficient mutations in regulatory motifs of Ypk3 abrogate Rps6 phosphorylation, and complementation of ypk3Δ cells with human S6 kinase restores Rps6 phosphorylation in a rapamycin-sensitive manner. Our findings demonstrate that Ypk3 is a critical component of the TORC1 pathway and that the use of a phospho-S6 specific antibody offers a valuable tool to identify new nutrient-dependent and rapamycin-sensitive targets in vivo.

SummaryThe inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn) complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway.

Background Environmental exposures to indoor allergens are major contributors to asthma symptoms, particularly in inner cities. The effectiveness of household allergen reduction as an adjunct to National Asthma Education Prevention Program (NAEPP) guideline-based pharmacologic therapy in asthma has not been prospectively studied. Objective We studied the effect of individualized allergen reduction on ability to reduce asthma pharmacologic therapy over 40 weeks. Methods We performed a randomized, controlled trial to determine the effect of multi-faceted indoor allergen avoidance measures on ability to reduce asthma controller therapy in adults and children residing in New York City who were both sensitized and exposed to at least one indoor allergen. Asthma treatment and control were optimized in all subjects prior to randomization. Results 125 subjects were randomized to receive individualized household allergen reduction and 122 received a sham intervention. Subjects in the intervention group significantly reduced all measured allergen levels (cat, dog, dust mite in the bedroom, roach and mouse in the kitchen and bedroom); those in the control group reduced only dust mite and mouse in the bedroom and roach in the kitchen. Participants in the intervention arm reduced NAEPP based therapy from step 4.4 at randomization to 3.50 post intervention (range 0–6); participants in the control arm reduced medication from step 4.4 to 3.4 (p = 0.76). There were no differences in other measured asthma outcomes. Conclusion Targeted allergen avoidance measures do not allow for reduction in asthma pharmacologic therapy compared to usual care in patients already receiving optimal controller therapy.

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