Physical Interaction between Embryonic Stem Cell-Expressed Ras (ERas) and Arginase-1 in Quiescent Hepatic Stellate Cells
Silke Pudewell,
Jana Lissy,
Hossein Nakhaeizadeh,
Mohamed S. Taha,
Mohammad Akbarzadeh,
Soheila Rezaei Adariani,
Saeideh Nakhaei-Rad,
Junjie Li,
Claus Kordes,
Dieter Häussinger,
Roland P. Piekorz,
Miriam M. Cortese-Krott,
Mohammad Reza Ahmadian
Affiliations
Silke Pudewell
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Jana Lissy
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Hossein Nakhaeizadeh
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Mohamed S. Taha
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Mohammad Akbarzadeh
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Soheila Rezaei Adariani
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Saeideh Nakhaei-Rad
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Junjie Li
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Claus Kordes
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40225 Düsseldorf, Germany
Dieter Häussinger
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40225 Düsseldorf, Germany
Roland P. Piekorz
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Miriam M. Cortese-Krott
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Mohammad Reza Ahmadian
Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Embryonic stem cell-expressed Ras (ERas) is an atypical constitutively active member of the Ras family and controls distinct signaling pathways, which are critical, for instance, for the maintenance of quiescent hepatic stellate cells (HSCs). Unlike classical Ras paralogs, ERas has a unique N-terminal extension (Nex) with as yet unknown function. In this study, we employed affinity pull-down and quantitative liquid chromatography-tandem mass spectrometry (LC–MS/MS) analyses and identified 76 novel binding proteins for human and rat ERas Nex peptides, localized in different subcellular compartments and involved in various cellular processes. One of the identified Nex-binding proteins is the nonmitochondrial, cytosolic arginase 1 (ARG1), a key enzyme of the urea cycle and involved in the de novo synthesis of polyamines, such as spermidine and spermine. Here, we show, for the first time, a high-affinity interaction between ERas Nex and purified ARG1 as well as their subcellular colocalization. The inhibition of ARG1 activity strikingly accelerates the activation of HSCs ex vivo, suggesting a central role of ARG1 activity in the maintenance of HSC quiescence.
