title: Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling.
abstract: 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.
authors.forename: Ephraim A
authors.initials: EA
authors.lastname: Ansa-Addo
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: George S
authors.initials: GS
authors.lastname: Hussey
authors.forename: Breege V
authors.initials: BV
authors.lastname: Howley
authors.forename: Mohammad
authors.initials: M
authors.lastname: Salem
authors.forename: Brian
authors.initials: B
authors.lastname: Riesenberg
authors.forename: Shaoli
authors.initials: S
authors.lastname: Sun
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
authors.forename: Serhan
authors.initials: S
authors.lastname: Karvar
authors.forename: Philip H
authors.initials: PH
authors.lastname: Howe
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D011485:Protein Binding; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D021381:Protein Transport; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*; D019139:Tumor Escape; D015854:Up-Regulation
chemical_list: D008840:Microfilament Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C071058:moesin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II