Biology subjects

Rutter, J.

Publications and source records attributed to Rutter, J..

40 records · Page 3Linked to original sources

bioRxiv2018

Vms1p is a release factor for the Ribosome-associated Quality control Complex

Eukaryotic cells employ the Ribosome-associated Quality control Complex (RQC) to maintain homeostasis despite defects that cause ribosomes to stall. The RQC comprises the E3 ubiquitin ligase Ltn1p, the ATPase Cdc48p, and the novel proteins Rqc1p and Rqc2p1-3. Following recognition and subunit splitting of stalled ribosomes, the RQC detects and assembles on 60S subunits that hold incomplete polypeptides linked to a tRNA (60S:peptidyl-tRNA)4-8. Ltn1p cooperates with Rqc1p to facilitate ubiquitination of the incomplete nascent chain, marking it for degradation7,9,10. Rqc2p stabilizes Ltn1p on the 60S3-5,8 and recruits charged tRNAs to the 60S to catalyze elongation of the nascent protein with Carboxy-terminal Alanine and Threonine extensions, or CAT tails, via a mechanism that is distinct from canonical translation4,10. CAT-tailing mobilizes and exposes lysine residues in the nascent chain, especially those stalled within the exit tunnel, thereby supporting efficient ubiquitination10,11. If the ubiquitin-proteasome system is overwhelmed or unavailable, CAT-tailed nascent chains aggregate in the cytosol or within organelles like the mitochondria12-14. Here we identify Vms1p as the tRNA hydrolase that releases nascent polypeptides for extraction and degradation in the RQC pathway.

biochemistry↗

bioRxiv2017

mTORC1 activates PASK-Wdr5 signaling to epigenetically connect the nutrient status with myogenesis.

In the tissue microenvironment, stem cell functions are modulated by extrinsic signaling cues such as peptide hormones and dietary nutrients. These signaling cues maintain the balance between self-renewal and differentiation of its resident stem cells. The mechanistic Target of Rapamycin Complex 1 (mTORC1) is implicated to play an important role in regulating this balance, although its downstream effectors in stem cells have been elusive. We have recently shown that the PASK protein kinase phosphorylates Wdr5 to stimulate muscle stem cell differentiation by epigenetically activating the Myogenin promoter. Here, we show that the PASK-Wdr5 signaling pathway is a nutrient-sensitive downstream target of mTORC1 in muscle stem cells. We show that phosphorylation of PASK, and in turn of Wdr5, by mTORC1 is required for the activation of Myogenin transcription, exit from the self-renewal and induction of the myogenesis program. Thus, mTOR connects the diverse extrinsic signaling cues to a central epigenetic process to regulate the muscle stem cell fate between self-renewal and differentiation.

cell biology↗

bioRxiv2017

Collateral sensitivity is contingent on the repeatability of evolution

Antibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of collateral sensitivities, wherein evolution under a first drug induces susceptibility to a second. Here, we report that sequential drug regimens derived from in vitro evolution experiments may have overstated therapeutic benefit, predicting a collaterally sensitive response where cross resistance ultimately occurs. We quantify the likelihood of this phenomenon by use of a mathematical model parametrised with combinatorially complete fitness landscapes for Escherichia coli. Through experimental evolution we then verify that a second drug can indeed stochastically exhibit either increased susceptibility or increased resistance when following a first. Genetic divergence is confirmed as the driver of this differential response through targeted and whole genome sequencing. Taken together, these results highlight that the success of evolutionarily-informed therapies is predicated on a rigorous probabilistic understanding of the contingencies that arise during the evolution of drug resistance.

evolutionary biology↗

bioRxiv2017

Global analysis of plasma lipids identifies liver-derived acyl-carnitines as a fuel source for brown fat thermogenesis

Cold induced thermogenesis is an energy demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted LC-MS based lipidomics, we identified plasma acylcarnitines as the most significantly changed lipid class in response to the cold. Here we show that acylcarnitines provide fuel for brown fat thermogenesis. In response to the cold, FFAs released from adipocytes activate the nuclear receptor HNF4 to stimulate the expression of genes involved in acylcarnitine metabolism in the liver. Conditional deletion of HNF4 in hepatocytes blocks the cold-induced changes in hepatic gene expression, lowering circulating long chain acylcarnitine (LCAC) levels, and impairing their ability to adapt to the cold. Finally, a bolus of L-carnitine or palmitoylcarnitine rescues the cold sensitivity seen with aging. Our data highlights an elegant mechanism whereby white adipose tissue provides FFAs for hepatic carnitilation to generate plasma LCAC as a fuel source for BAT thermogenesis.\n\nHighlightsO_LIBlood acylcarnitine levels increase in response to the cold.\nC_LIO_LIFFA mobilization in response to the cold activates hepatic HNF4 and stimulates genes involved in acylcarnitine metabolism.\nC_LIO_LIBrown adipocytes metabolize palmitoylcarnitine.\nC_LIO_LICarnitine administration improves thermogenic response in aged mice.\nC_LI\n\nETOCSimcox et al identified acylcarnitines as a novel source of energy for thermogenesis. In response to the cold, the liver activates a transcriptional program through the transcription factor HNF4, leading to increased acylcarnitine levels. They also find that aging mice have reduced acylcarnitine levels and an impaired thermogenic response in the cold. Increasing acylcarnitine levels in old mice increases their ability to adapt to the cold. Their studies discover a physiological role for acylcarnitines in thermogenesis.\n\nGraphical AbstractCold exposure stimulates the sympathetic nervous system to release noradrenaline (NA). Activation of {beta}3-adrenergic receptors stimulates FFA release and activation of the transcription factor HNF4 in the liver. This leads to increased gene expression of enzymes involved in acylcarnitine metabolism. The acylcarnitines are released in the blood to provide fuel for brown fat thermogenesis. These studies highlight the role of the liver in the thermogenic response.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC=\"FIGDIR/small/132241_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (80K):\norg.highwire.dtl.DTLVardef@1282891org.highwire.dtl.DTLVardef@17f7c7forg.highwire.dtl.DTLVardef@c6b637org.highwire.dtl.DTLVardef@1e4f40d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗