Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling

Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that are important for organizing membrane domains and receptor signaling and regulating the migration of effector T cells. Whether moesin plays any role during the generation of TGF-β-induced Tregs (iTregs) is unknown. Here, we...

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Bibliographic Details
Published in:The Journal of clinical investigation 2017-04, Vol.127 (4), p.1321-1337
Main Authors: Ansa-Addo, Ephraim A, Zhang, Yongliang, Yang, Yi, Hussey, George S, Howley, Breege V, Salem, Mohammad, Riesenberg, Brian, Sun, Shaoli, Rockey, Don C, Karvar, Serhan, Howe, Philip H, Liu, Bei, Li, Zihai
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
Cell Differentiation
Cell Membrane - metabolism
Cells, Cultured
Female
HEK293 Cells
Humans
Male
Melanoma, Experimental - immunology
Melanoma, Experimental - pathology
Melanoma, Experimental - therapy
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Microfilament Proteins - physiology
Neoplasm Transplantation
Protein Binding
Protein Biosynthesis
Protein Stability
Protein Transport
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta - genetics
Receptors, Transforming Growth Factor beta - metabolism
Signal Transduction
Skin Neoplasms - immunology
Skin Neoplasms - pathology
Skin Neoplasms - therapy
T-Lymphocytes, Regulatory - physiology
Transcriptional Activation
Transforming Growth Factor beta - physiology
Tumor Escape
Up-Regulation
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Summary:Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that are important for organizing membrane domains and receptor signaling and regulating the migration of effector T cells. Whether moesin plays any role during the generation of TGF-β-induced Tregs (iTregs) is unknown. Here, we have discovered that moesin is translationally regulated by TGF-β and is also required for optimal TGF-β signaling that promotes efficient development of iTregs. Loss of moesin impaired the development and function of both peripherally derived iTregs and in vitro-induced Tregs. Mechanistically, we identified an interaction between moesin and TGF-β receptor II (TβRII) that allows moesin to control the surface abundance and stability of TβRI and TβRII. We also found that moesin is required for iTreg conversion in the tumor microenvironment, and the deletion of moesin from recipient mice supported the rapid expansion of adoptively transferred CD8+ T cells against melanoma. Our study establishes moesin as an important regulator of the surface abundance and stability of TβRII and identifies moesin's role in facilitating the efficient generation of iTregs. It also provides an advancement to our understanding about the role of the ERM proteins in regulating signal transduction pathways and suggests that modulation of moesin is a potential therapeutic target for Treg-related immune disorders.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI89281