title: Class I myosin Myo1e regulates TLR4-triggered macrophage spreading, chemokine release, and antigen presentation via MHC class II.
abstract: TLR-mediated recognition of microbial danger induces substantial changes in macrophage migration, adherence, and phagocytosis. Recently, we described the LPS-regulated phosphorylation of many cytoskeleton-associated proteins by phosphoproteomics. The functional role of these cytoskeletal and motor proteins in innate immune cell responses is largely unexplored. Here, we first identified both long-tailed class I myosins Myo1e and Myo1f as important contributors to LPS-triggered macrophage spreading. Mouse bone marrow-derived macrophages and DCs deficient in Myo1e selectively secreted increased amounts of the chemokine CCL2. In addition, the cell surface expression of MHC class II (MHC-II) on both cell types was reduced in the absence of Myo1e. However, transcriptional changes in CCL2 and MHC-II were not observed in the absence of Myo1e, indicating that Myo1e regulates specific intracellular transport processes. The capacity of macrophages and DCs lacking Myo1e to stimulate antigen-specific CD4(+) T-cell proliferation was impaired, consistent with the reduced MHC-II surface protein levels. Surprisingly, in Myo1e-deficient DCs, the proteolytic cleavage of endocytosed antigen was also increased. Together, our results provide evidence for a non-redundant function of the motor protein Myo1e in the regulation of TLR4-controlled, cytoskeleton-associated functional properties of macrophages and DCs, and in induction of a full MHC-II-restricted adaptive immune response.
authors.affiliation: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wenzel
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ouderkirk
authors.forename: Mira
authors.initials: M
authors.lastname: Krendel
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D003599:Cytoskeleton / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024461:Myosin Type I / Q000235:genetics / Q000276:immunology; D009218:Myosins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; C514128:Myo1f protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C505821:Myo1e protein, mouse; D024461:Myosin Type I; D009218:Myosins
keywords: Cytoskeleton; MHC class II; Macrophages; Myosin; Toll-like receptors