Ro52 in innate immunity, proliferation control and cancer
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- Kajetan Braun
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1 Diss. ETH No Ro52 in innate immunity, proliferation control and cancer Andrea Michael Meyer Diss. ETH No Ro52 in innate immunity, proliferation control and cancer A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences presented by ANDREA MICHAEL MEYER Dipl. Natw. ETH, ETH Zurich citizen of Zurich Accepted on the recommendation of Prof. W. Krek Prof. J. Jiricny Prof. M. Peter Prof. J. Tschopp 2009
2 Diss. ETH N o Ro52 in innate immunity, proliferation control and cancer A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences presented by ANDREA MICHAEL MEYER Dipl. Natw. ETH, ETH Zurich citizen of Zurich Accepted on the recommendation of Prof. W. Krek Prof. J. Jiricny Prof. M. Peter Prof. J. Tschopp 2009
3 Abstract Cells constantly monitor their environment for signals such as growth factors, hormones, nutrients and pathogens. A vast network of intracellular pathways tightly regulates the responses to environmental cues. Examples for cellular responses include growth arrest, onset of proliferation or the induction of antiviral defense mechanisms of the innate immune system. In the course of this work, we identified Ro52 as a key protein, which displays ubiquitin ligase activity, to be involved in pathways regulating proliferation and processes of the innate immune system. Ubiquitin is a small, highly conserved protein found in all eukaryotes. It is covalently attached to substrate proteins by ubiquitin ligases as an earmark for degradation or as a posttranslational modification in the course of signaling events. Ubiquitin-mediated degradation of the cyclin-dependent kinase (CDK) inhibitor p27 provides a powerful route to enforce normal progression through the mammalian cell cycle. According to a current model, ubiquitination of p27 during S phase progression is mediated by SCF Skp2 E3 ligase that captures Thr187-phosphorylated p27 by means of the F-box protein Skp2, which in turn, couples the bound substrate via Skp1 to a catalytic core complex composed of Cul1 and the Rbx/Roc RING finger protein. Here we identify Ro52 as a component of an SCF-like complex, that is based on a Cul1-Ro52 RING finger B-box coiled-coil (RBCC) motif family protein catalytic core. Ro52-containing complexes display E3 ligase activity and promote ubiquitination of Thr187-phosphorylated p27 in a RING-dependent manner in vitro. Knockdown of Ro52 expression in human cells with small interfering RNAs (sirna) causes accumulation of p27 and failure of cells to enter S phase. Importantly, these effects are abrogated by the simultaneous removal of p27. Taken together, these data suggest a key role for Ro52 RING finger protein in the regulation of p27 degradation and S phase progression in mammalian cells and provide evidence for the existence of a Cul1-based catalytic core that utilizes Ro52 RING protein to promote ubiquitination. Defective cell cycle is a hallmark of malignances. Since Ro52 is involved in the regulation of G1/S-phase transition we suspected it to be a protein involved in malignant disease development and/or progression. Immunohistochemical analysis of mamma carcinoma and melanoma cancer tissue microarrays revealed a tight association of Ro52 signal with the proliferation marker protein Ki-67, with major histocompatibility complex I 11
4 (MHC-I), and signal transducer and activator of transcription 1 (Stat1) signal. The strong correlation of Ro52 signal with Ki-67 signal indicates a role of Ro52 in proliferation control in malignant disease. The correlation of Ro52 with MHC-I, a transcriptional target of Stat1, and with Stat1 itself indicates a participation of Ro52 in innate immune mechanisms. To gain insights in the in vivo function of Ro52, we generated Ro52 knockout mice. Unchallenged mice did not show major defects. They appeared healthy and fertile under specific pathogen free conditions although in two aged mice markedly enlarged spleens were found. Importantly, Western blot analysis revealed strongly reduced Stat1 protein abundance in knockout compared to wild-type animals. These findings also point towards a role of Ro52 in Stat1 signaling. Based on these observations we hypothesized a role of Ro52 in innate immunity and in particular in interferon signaling. Exposure of cells to interferon-" (INF") leads to the activation of the transcriptional activator Stat1 and thereby to the induction of a range of genes involved in innate immunity. We found that INF" induces Ro52 expression in multiple human cell lines and in vivo. Knockdown of Ro52 by RNAi in HeLa cells identified Ro52 as a potent positive regulator of INF" signaling. The INF" inducible genes ISG15, IFIT3 and ISG54 were markedly less activated in Ro52 depleted cells than in control cells upon INF" administration, as was assessed by quantitative PCR. We observed a reduction in transcript numbers to 30 to 50% for the genes tested. Similar effects were found in Ro52 knockout primary peritoneal macrophages compared to wild-type cells. Ro52 RNAi on human cells showed reduced Stat1 protein signal in Western blot analysis as was confirmed in vivo by analyzing knockout mouse primary cells and tissue lysates. This effect was rescued by overexpression of human Ro52 in knockout mouse embryonic fibroblasts. Therefore we could clearly show the Ro52-dependency of this phenotype. Additionally, Ro52 depletion led to a significantly decreased number of IRF-1 transcripts, both in human cells and in vivo, indicating a shift in the steady state of the auto-regulatory loops involved, since Stat1 regulates IRF-1 transcription and vice versa. Thus, we identified Ro52 to be the core of an SCF-like E3 ligase involved in proliferation control by ubiquitinating p27 and in parallel to be an important positive regulator of Stat1 and INF" signaling. Therefore we provide first evidence that the proliferation machinery and the antiviral defense machinery converge in Ro52 in order to presumably shorten the signaling events necessary for switching a cells course from proliferation to antiviral state and thereby narrowing the window of opportunity for a pathogen attack. 12
5 Zusammenfassung Zellen überwachen andauernd ihre Umwelt auf Veränderungen in der Zusammensetzung der Wachstumsfaktoren, Hormone, Nährstoffe oder das Auftreten von Pathogenen. Ein komplexes Netzwerk intrazellulärer Signalwege reguliert die Antwort auf Veränderungen in der Umwelt. Mögliche Reaktionen einer Zelle sind das Anhalten des Zellzyklus, das Vorantreiben des Zellzyklus oder die Aktivierung der Mechanismen der angeborenen Immunabwehr zur Bekämpfung viraler Infektionen. Im Zuge der vorliegenden Doktorarbeit entdeckten wir, dass Ro52, ein Protein mit Ubiquitinligase-Aktivität, eine wichtige Rolle in der Regulation der Zellproliferation und der angeborenen Immunabwehr spielt. Ubiquitin ist ein kleines hochkonserviertes Protein, das in allen Eukaryoten vorkommt. Es wird durch Ubiquitinligasen in langen Ketten, bestehend aus Ubiquitinuntereinheiten, auf Substratproteine übertragen, die so für die proteasomale Degradation markiert werden. Eine Ausnahme dazu bildet die Monoubiquitinierung, die der Signaltransduktion dienen kann. Eine wichtige Bedingung für das normale Durchlaufen des Zellzykluses ist der Ubiquitin-abhängige Abbau des Zellzyklus-inhibierenden Proteins p27. Gemäß der allgemeinen gegenwärtigen Auffassung, wird Thr187-phosphoryliertes p27 durch die SCF Skp2 Ubiquitinligase über das F-box Protein Skp2 erkannt, welches selbst über Skp1 an die E3 Ligase gekoppelt ist. Dadurch wird das Substrat, das ubiquitiniert werden soll, zum katalytische Zentrum geleitet, welches aus Cul1 und dem RING Finger Protein Rbx/Roc besteht. Im Laufe dieser Arbeit, entdeckten wir, dass Ro52 Teil eines SCF-ähnlichen Komplexes ist, der in seinem katalytischen Zentrum Cul1 und das RING Finger Protein Ro52 aufweist. Ro52 ist ein Mitglied der RING finger- Bbox- coiled-coil (RBCC) Proteinfamilie. Die Ro52-enthaltenden Proteinkomplexe haben Ubiquitin E3 Ligaseaktivität und ubiquitinieren Thr187-phosphoryliertes p27 RING-abhängig. Die Anwendung von RNA Interferenz (RNAi) gegen Ro52 führt zu einer Anreicherung von p27 und vermindert das Fortschreiten des Zellzyklus in die S-Phase. Dieser Effekt konnte durch das gleichzeitige Entfernen von p27 überwunden werden. Zusammenfassend lässt sich sagen, dass das RING Finger Protein Ro52 eine Schlüsselrolle in der Regulation der Degradation von p27 und der S-Phaseprogression von Säugerzellen einnimmt und Teil des katalytischen Zentrums einer neuartigen Cul1 basierten E3 Ligase ist. 13
6 Defekte in der Regulation des Zellzyklus sind typisch für Krebserkrankungen. Da Ro52 in die Kontrolle des G1/S-Phase-Übergangs involviert ist, liegt die Vermutung nahe, dass Ro52 in der Entstehung und/oder im Fortschreiten von Krebserkrankungen eine Rolle spielen könnte. Wir untersuchten Mammakarzinom- und Melanom- Gewebe-Mikro-Arrays immunohistochemisch. Dabei entdeckten wir eine hohe Korrelation in der Expression von Ro52 und dem Proliferationsmarker Ki67. Dies weist auf eine Rolle von Ro52 in der Proliferationskontrolle auch in Krebserkrankungen hin. Ro52 korreliert ebenfalls stark mit MHC-I, einem Protein, das durch den Transkriptionsfaktor Stat1 reguliert wird und eine wichtige Rolle in der Immunabwehr spielt. Ro52 korreliert auch mit Stat1. Dies deutet auf einen Zusammenhang zwischen Ro52 und Stat1-Signaltransduktion hin. Um vermehrt Einsicht in die Funktion von Ro52 auch im organismischen Kontext, also in vivo zu gewinnen, wurden Ro52 knockout-mäuse generiert. Die Ro52 knockout- Mäuse sind gesund, fertil und haben keine augenfällige Defekte, außer, dass in zwei alten Mäusen eine markante Vergrößerung der Milz angetroffen wurde. Western blot Analysen zeigten aber eine deutliche Verringerung der Stat1-Proteinmenge in Primärzellen aber auch in Organen dieser Mäuse im Vergleich zu wildtyp-mäusen. Basierend auf unseren bisherigen Erkenntnissen stellten wir die Hypothese auf, dass Ro52 eine Funktion in der angeborenen Immunabwehr und im Speziellen in der Interferon (INF) Signaltransduktion haben könnte. Wir fanden heraus, dass Ro52 in menschlichen Zellen und in vivo in der Maus, nach einer Behandlung mit INF", stark induziert wird und zwar sowohl auf Transkript- als auch auf Proteinebene. RNAi-Experimente identifizierten Ro52 als potenten positiven Regulator von INF" Signaltransduktion. In Zellen, in denen Ro52 durch RNAi stark verringert wurde, wurden die INF-induzierbaren Proteine ISG15, IFIT3 und ISG54 viel weniger stark durch INF" aktiviert als in den Kontrollzellen. Eine Verringerung auf 30 bis 50% wurde mittels quantitativer PCR beobachtet. Ähnliche Resultate lieferte das analoge Experiment mit primären peritonealen Makrophagen aus Knockout- im Vergleich zu Wildtyp-Mäusen. Ro52 RNAi auf humanen Zellen führte ebenfalls zu reduziertem Stat1 Proteinsignal in Western blot, was durch die in vivo Daten von der Knockout-Maus bestätigt wurde. Dieser Effekt konnte durch die Überexpression von humanem Ro52 in primären Mausfibroblasten kompensiert werden. Zusätzlich wurde eine Verringerung der Anzahl IRF-1 Transkripte detektiert wenn Ro52 durch RNAi oder durch Knockout entfernt wurde. Dies deutet auf eine Verlagerung des Gleichgewichts der 14
7 involvierten autoregulatorischen Rückkopplungsmechanismen hin, da Stat1 die IRF-1 Expression reguliert und umgekehrt. Abschließend kann gesagt werden, dass Ro52 einerseits ein wichtiger Bestandteil des katalytischen Zentrums einer SCF-ähnlichen Ubiquitinligase ist, die den Zellzyklusinhibitor p27 abbaut. Gleichzeitig aber hat Ro52 eine wichtige Funktion als positiver Regulator von Stat1 und der INF" Signaltransduktion inne. Wir liefern hiermit zum ersten Mal Anhaltspunkte, dass die Proliferationsmaschinerie und die antivirale Abwehrmaschinerie in Ro52 konvergieren. Der Grund für diese Konvergenz könnte sein, dass dies ein möglichst schnelles und effizientes Umschalten der Zellen von Proliferation in den sogenannten antiviralen Zustand ermöglicht und somit das Zeitfenster für einen Virenbefall stark verringert wird. 15
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