Mammalian diaphanous-related formin 1 regulates GSK3β-dependent microtubule dynamics required for T cell migratory polarization

• Published in: PloS one 2013-11, Vol.8 (11), p.e80500-e80500
• Main Authors: Dong, Baoxia, Zhang, Steven S, Gao, Wen, Su, Haichun, Chen, Jun, Jin, Fuzi, Bhargava, Ajay, Chen, Xiequn, Jorgensen, Lars, Alberts, Arthur S, Zhang, Jinyi, Siminovitch, Katherine A
• Format: Article
• Language: English
• Subjects: Adenomatous polyposis coli; Adenomatous Polyposis Coli Protein; Adhesion; Animals; Antigen-presenting cells; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell adhesion; Cell adhesion & migration; Cell migration; Cell Movement - genetics; Cell Movement - immunology; Cell Polarity - genetics; Cell Polarity - immunology; Chemokines; Chemotaxis; Clustering; Cytoskeleton; Deactivation; Defects; Departments; Enzyme Activation; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Hematology; Immunology; Inactivation; Intercellular Adhesion Molecule-1 - metabolism; Kinases; Leukocyte migration; LFA-1 antigen; Lymphatic system; Lymphocyte Activation - immunology; Lymphocyte Function-Associated Antigen-1 - genetics; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphocytes; Lymphocytes T; Mammals; Mice; Mice, Knockout; Microtubules - metabolism; Morphology; Motility; Phosphorylation; Polarity; Polarization; Polyposis coli; Protein Binding; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0080500

The mammalian diaphanous-related formin (mDia1), a Rho-regulated cytoskeletal modulator, has been shown to promote T lymphocyte chemotaxis and interaction with antigen presenting cells, but the mechanisms underpinning mDia1 roles in these processes have not been defined. Here we show that mDia1(-/-) T cells exhibit impaired lymphocyte function-associated antigen 1 (LFA-1)-mediated T cell adhesion, migration and in vivo trafficking. These defects are associated with impaired microtubule (MT) polarization and stabilization, altered MT dynamics and reduced peripheral clustering of the MT plus-end-protein, adenomatous polyposis coli (APC) in migrating T cells following LFA-1-engagement. Loss of mDia1 also leads to impaired inducible inactivation of the glycogen synthase kinase (GSK) 3β as well as hyperphosphorylation and reduced levels of APC in migrating T cells. These findings identify essential roles for the mDia1 formin in modulating GSK3β-dependent MT contributions to induction of T-cell polarity, adhesion and motility.