The metabolic regulator mTORC1 controls terminal myeloid differentiation
Year: 2017
Type: article
Abstract: cr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage. Conversely, excess activation of mTORC1 through deletion of the mTORC1 inhibitor tuberous sclerosis complex 2 promoted spontaneous myeloid cell development and maturation. Inhibitor studies and stage-specific expression profiling identified failure to down-regulate the transcription factor Myc by the mTORC1 target ribosomal S6 kinase 1 (S6K1) as the mechanistic basis for disrupted myelopoiesis. Together, these findings define the mTORC1-S6K1-Myc pathway as a key checkpoint in terminal myeloid development.
Source: Science Immunology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: American College of Rheumatology Research and Education Foundation, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1064273827, G1121906653, Role of CX3CR1 in adaptive immunity during autoimmune encephalomyelitis, G1515592102, G3287319054, mTOR Complexes in Hematopoiesis, Ly6 family members in neutrophil biology, G4825779756, G5043643491, G5130393897, C5a receptor on mast cells in inflammatory arthritis, Osteoclast precursors in bone homeostasis and inflammatory arthritis, Functional consequences of stem and progenitor cell heterogeneity, Molecular Basis of Allergic and Immunologic Disease, Immunologic Mechanisms and Rheumatic Diseases, Joint Biology Consortium Resource-based Center
OpenAlex ID: W2618407046