University of Connecticut

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CCAM Seminar Series - Ditlev

Thursday, January 28, 2021
12:00pm – 1:00pm

UConn Health

CCAM Seminar Series Time: 12:00 pm Host: Dr. Bruce Mayer Speaker: Jonathon Ditlev, Ph.D., Assistant Professor, Department of Biochemistry, University of Toronto, Scientist, Molecular Medicine Program, The Hospital for Sick Children Title: “Phase separation: a paradigm shift for understanding the formation and function of T cell signaling clusters” Abstract: In T cells, activation of many cell surface receptors induces the reorganization of downstream signaling molecules into submicrometer-sized clusters. Upon binding of the T cell receptor to an agonist on an antigen presenting cell, a series of phosphorylation events promotes clustering of the membrane-localized adaptor protein LAT. Subsequently, LAT clusters are moved across the membrane of the T cell by two different concentric actin cytoskeletal networks. This dynamic process is required for proper T cell signaling. However, the mechanism by which LAT clusters form, the functional consequences of clustering, and the mechanism by which clusters are moved by two distinct actin cytoskeletal networks were unclear. The signaling pathway, beginning with the T cell receptor and ending with actin assembly, was reconstituted on model membranes. Triggering of T cell receptor phosphorylation resulted in the formation of membrane-localized liquid-like phase separated clusters composed of signaling molecules that promoted signaling outputs in biochemical reconstitutions and human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases, promoted local actin assembly by recruiting actin nucleation machinery, and displayed compositional-dependent interactions with dynamic actomyosin networks. When Nck and its binding partner N-WASP were present in clusters, clusters bound to and moved with dynamic actin filaments. Clusters lacking these components were instead sterically propelled by moving actin filaments. In cells, Nck dissipates from LAT clusters as they are moved across the boundary between the two actin networks. This change in composition likely enables cluster movement by the distinct dynamics of each network to promote T cell signaling. Thus, phase separation of LAT and its binding partners promotes signal propagation from clusters while compositional changes within the clusters enable them to be moved by two distinct actin networks to maintain proper T cell signaling. The principles revealed by these studies likely apply to the numerous two- and three-dimensional phase separated structures that exist within a cell. Meeting link: Meeting number: 120 463 0186 Password: EJnJ9Y8s6VP Host key: 583108 More ways to join Join by video system Dial You can also dial and enter your meeting number. Join by phone +1-415-655-0002 US Toll Access code: 120 463 0186



Center for Cell Analysis and Modeling (primary), School of Medicine

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