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The Role of PASKIN in Metabolism and Protein Synthesis Philipp Schläfli

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The Role of PASKIN in Metabolism and Protein Synthesis Philipp Schläfli Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2011 The role of PASKIN in metabolism and protein synthesis Schläfli, Philipp Abstract: PER-ARNT-SIM (PAS) Domänen sind in Organismen verbreitet. In Bakterien und Archaeen fungieren sie hauptsächlich als sensorische Module für eine Vielzahl von Umwelteinflüssen. Dies geschieht entweder direkt durch Binden des zu detektierenden Liganden oder indirekt unter Verwendung eines Kofaktors. Dabei induziert die Detektion Veränderungen in der Konformation der PAS-Domäne, welche das Signal zu einer Effektordomäne, häufig einer Kinase, weiterleitet. In Eukaryoten, insbesondere inba- sic helix-loop-helix Transkriptionsfaktoren, ermöglichen PAS-Domänen oftmals das Dimerisieren zweier Proteine. Das PASKIN-Protein besitzt die für Eukaryoten einzigartige Kombination einer PAS-Domäne und einer Serin/Threonin Kinase und ist von der Hefe bis zum Menschen konserviert. Für die PAS- Domäne von PASKIN wurde ein Modell propagiert, gemäss welchem ein unbekannter metabolischer Ligand detektiert wird, worauf die Kinasefunktion aktiviert wird. Erste Hinweise für die Kinasefunktion stammen aus der Hefe, wo PASKIN Proteine aus dem Glycogenmetabolismus und der Proteintransla- tion phosphorylieren kann. In Säugern wurden bislang zwei durch PASKIN phosphorylierte Proteine aus dem Metabolismus entdeckt. Das Erste, wie in der Hefe, ist die Glykogensynthase, und das zweite ist das pankreatische und duodenale Homeobox Protein 1 (PDX-1), ein wichtiger Transkriptionsfak- tor für die Insulinexpression. Entsprechend wurde publiziert, dass PASKIN in ฀-Zellen des Pankreas durch Glukose induziert werden kann. Dies führt zu einer erhöhten Insulinexpression und sekundär zu gesteigerter Insulinsekretion. Neueste Erkentnisse haben auch eine inhibitorische Funktion von PASKIN in der Glukagonsekretion aufgezeigt. Aufgrund all dessen wird angenommen, dass PASKIN nicht nur den Energiehaushalt der Hefe reguliert, sondern auch den von höheren Lebewesen. Des Weiteren wurde auch die Homöostase auf der Ebene des Gesamtorganismus untersucht, wobei unsere Paskin-/- Mäuse verwen- det wurden. Nach Fütterung einer Hochfettdiät waren Paskin-/- Männchen vor nachteiligen Erscheinun- gen des metabolischen Syndroms teilweise geschützt. So zeigten sie ein reduziertes Körpergewicht und bessere Glukose- und Insulintoleranz auf als Wildtyptiere und hatten einen hypermetabolischen Phäno- typ in Messungen der indirekten Kalorimetrie. In dieser Arbeit hatten wir uns zum Ziel gesetzt, diesen Phänotypen zu reproduzieren. Tatsächlich führte die Fütterung einer Hochfettdiät (45% kalorisches Fett) zu reduziertem Körpergewicht und besserer Glukosetoleranz. Mit der Fütterung einer Hochfettdiät mit 60% kalorischem Fett konnten wir diese Effekte jedoch nicht verstärken. Auch die indirekte Kalorimetrie und Messungen der Körpertemperatur bestätigten den hyperetabolischen Phänotyp nicht. Wir glauben deshalb, dass PASKIN eine sehr subtile Rolle in der Regulierung des Energiehaushaltes spielt, welche von kleinen Unterschieden in der Tierhaltung, der Nahrung oder dem Alter beeinflusst wird. Aufgrund dessen haben wir uns vermehrt auf die Beantwortung von molekularen und zellulären Fragen konzentriert: 1) Was ist die Substratspezifität für die PASKIN-Phosphorylierung und was könnten neue Zielproteine im Metabolismus und der Proteintranslation sein? 2) Was könnte der aktivierende Ligand für die PAS- Domäne von PASKIN sein? In dieser Arbeit zeigen wir auf, dass der eukaryotische Elongationsfaktor 1A1 nicht nur ein Interaktionspartner von PASKIN ist, sondern auch phosphoryliert werden kann und damit die Translation in vitro verbessert. Um weitere von PASKIN phosphorylierbare Proteine zu ent- decken, haben wir ausserdem einen Peptidchip verwendet. Wir bestimmten die Substratspezifität, welche derer der Proteinkinasen A und C sehr ähnlich ist, und entdeckten neue metabolische Zielproteine. Wir konnten ausserdem zeigen, dass PASKIN das ribosomale Protein S6 an den Serinen 235/236 phospho- ryliert. Normalerweise wird S6 von p70 S6-Kinasen phosphoryliert. Deshalb gilt diese Phosphorylierung als Indikator für die Aktivität des mTOR-Signaltransduktionswegs und zeigt sich vorwiegend in prolif- erierenden Zellen. Beim Vergleich von Fibroblasten aus Mäuseembryonen von Paskin-/- und Paskin+/+ Mäusen konnten wir jedoch keine Unterschiede in der Proteintranslation, Zellgrösse oder dem Zellwachs- tum feststellen. Die Proteinkinase C weist nicht nur dieselbe Substratspezifität wie PASKIN auf, sondern phosphoryliert den eukaryotischen Elongationsfaktor 1A1 an genau demselben Threonin wie PASKIN. Deshalb stellten wir uns die Frage, ob PASKIN analog zu der Proteinkinase C, auch Phospholipide als Koaktivatoren benötigt. Tatsächlich fanden wir heraus, dass PASKIN an Phosphatidylinositolmonophos- phate bindet, allerdings nicht wie erwartet über die PAS-Domäne, sondern via Kinasedomäne. Daraufhin untersuchten wir den Einfluss von Phosphatidylinositolphosphaten auf die Autophosphorylierung und die Phosphorylierung von Zielproteinen von PASKIN. Interessanterweise induzierten monophosphorylierte Phosphatidylinositole die Autophosphorylierung von PASKIN, wohingegen di- und triphosphorylierte Phosphatidylinositole die Autophosphorylierung inhibierten. Hingegen inhibierten alle getesteten Phos- phatidylinositolphosphate die Phosphorylierung von Zielproteinen. Da wir ausserdem entdeckten, dass PASKIN entweder an der Zellmembran oder entlang des Aktinskeletts lokalisiert ist, nehmen wir an, dass PASKIN am Vesikeltransport oder dem Umbau des Zytoskeletts beteiligt sein könnte, und dabei durch die Bindung an Phospholipide reguliert wird. Abschliessend konnten wir aufzeigen, dass PASKIN durch die Phosphorylierung des Elongationsfaktors 1A1 und des ribosomalen Proteins S6 die Proteintranslation in höheren Lebewesen regulieren kann. Die Bindung an Phosphatidylinositolphosphate eröffnet ausserdem neue Perspektiven und könnte Erklärungen für den metabolischen Phänotyp liefern, so zum Beispiel über die Regulation der Glukagonsekretion oder der Exozytose von GLUT4 im Muskel. Weitere Befunde über die Expression oder Aktivierung von PASKIN würden mit Sicherheit das generelle Verständnis verbessern, wie PASKIN mechanistisch als Sensor des Energiehaushaltes agieren könnte. SUMMARY PER-ARNT- SIM (PAS) domains are occurring throughout all kingdoms of life. Bacterial and archaeal PAS domains mainly act as sensory modules of a variety of environmental stimuli either directly by binding a ligand to be sensed or indirectly involving co-factors. Sensing induces conformational changes of the PAS domain that are transduced to effector domains, which are often kinases. In other cases, especially in eukaryotic basic helix-loop-helix transcription factors, PAS domains can act as dimerisation interfaces. PASKIN is conserved from yeast to man and displays the unique combination for eukaryotic proteins of a Per-Arnt- Sim (PAS) domain and a Ser/Thr kinase function. For the PAS domain of PASKIN, a model proposed sensing and binding of a yet unknown metabolic ligand that might activate the kinase domain. For the kinase function, a number of proteins involved in glycogen metabolism and protein synthesis were iden- tified as phosphorylation targets in yeast. For mammalian PASKIN, two targets involved in metabolism have been identified. The first target, similar to yeast, is mammalian glycogen synthase, and thesecond target is pancreatic and duodenal homeobox protein 1 (PDX-1), an important transcription factor for insulin expression. Accordingly, it has been reported that PASKIN levels are induced in pancreatic ฀- cells upon glucose stimulation, itself induces insulin expression and secondarily affects insulin secretion. Recent findings also reported an inhibitory function of PASKIN in glucagon secretion, suggesting that PASKIN might regulate energy homeostasis not only in yeast, but in mammals as well. Furthermore, whole body homeostasis has been investigated making use of our Paskin-/- mouse model. It has been shown that male Paskin-/- mice when fed a high-fat diet (HFD) were protected from detrimental effects of the metabolic syndrome. Paskin-/- male mice displayed a lower body weight and a better glucose and insulin tolerance than wildtype littermates and showed a hypermetabolic phenotype in indirect calorime- try experiments. Using a similar approach, we herein aimed to reproduce the hypermetabolic phenotype on HFD feeding. Whereas we could see a lower gain of body weight for Paskin-/- animals and a better glucose tolerance after 45% fat by calories HFD feeding, we could not increase the effects upon feeding a 60% HFD and failed to see any difference in indirect calorimetry or body temperature. We therefore speculate that PASKIN might play a more subtle role in energy homeostasis that might be affected by housing, diet or age of the animals. We therefore focused on the molecular and cellular level aiming to answer the following questions: 1) What is the substrate specificity and what might be potential targets of metabolism and protein translation for the PASKIN kinase function? 2) What could be the poten- tially activating ligand for the PAS domain of PASKIN? Herein, we show that the human eukaryotic translation elongation factor 1A1 is a novel interaction partner and kinase target of PASKIN and is able to increase total translation in vitro. To screen for other putative PASKIN phosphorylation targets, we assessed the kinase function on a target
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