Central Role of ULK1 in Type I Interferon Signaling
Diana Saleiro,
Swarna Mehrotra,
Barbara Kroczynska,
Elspeth M. Beauchamp,
Pawel Lisowski,
Beata Majchrzak-Kita,
Tushar D. Bhagat,
Brady L. Stein,
Brandon McMahon,
Jessica K. Altman,
Ewa M. Kosciuczuk,
Darren P. Baker,
Chunfa Jie,
Nadereh Jafari,
Craig B. Thompson,
Ross L. Levine,
Eleanor N. Fish,
Amit K. Verma,
Leonidas C. Platanias
Affiliations
Diana Saleiro
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Swarna Mehrotra
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Barbara Kroczynska
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Elspeth M. Beauchamp
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Pawel Lisowski
Department of Molecular Biology, Institute of Genetics and Animal Breeding, 05-552 Jastrzebiec n/Warsaw, Poland
Beata Majchrzak-Kita
Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON M5G 2M1, Canada
Tushar D. Bhagat
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Brady L. Stein
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Brandon McMahon
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Jessica K. Altman
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Ewa M. Kosciuczuk
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Darren P. Baker
Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA
Chunfa Jie
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Nadereh Jafari
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Craig B. Thompson
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Ross L. Levine
Human Oncology and Pathogenesis Program, and Leukemia Service, Memorial Sloan Kettering Cancer Center; and Weill Cornell Medical College, New York, NY 10065, USA
Eleanor N. Fish
Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON M5G 2M1, Canada
Amit K. Verma
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Leonidas C. Platanias
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
We provide evidence that the Unc-51-like kinase 1 (ULK1) is activated during engagement of the type I interferon (IFN) receptor (IFNR). Our studies demonstrate that the function of ULK1 is required for gene transcription mediated via IFN-stimulated response elements (ISRE) and IFNγ activation site (GAS) elements and controls expression of key IFN-stimulated genes (ISGs). We identify ULK1 as an upstream regulator of p38α mitogen-activated protein kinase (MAPK) and establish that the regulatory effects of ULK1 on ISG expression are mediated possibly by engagement of the p38 MAPK pathway. Importantly, we demonstrate that ULK1 is essential for antiproliferative responses and type I IFN-induced antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms. Together, these data reveal a role for ULK1 as a key mediator of type I IFNR-generated signals that control gene transcription and induction of antineoplastic responses.
