Ditlev Jonathon

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Last Name
Ditlev
First Name
Jonathon
ORCID
0000-0001-8287-7700

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  • Preprint
    Phase separation of signaling molecules promotes T cell receptor signal transduction
    ( 2016-03) Su, Xiaolei ; Ditlev, Jonathon ; Hui, Enfu ; Xing, Wenmin ; Banjade, Sudeep ; Okrut, Julia ; King, David S. ; Taunton, Jack ; Rosen, Michael K. ; Vale, Ronald D.
    Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micron- or submicron-sized clusters. However, the functional consequences of such clustering has been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phoshophorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases, and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.
  • Article
    A composition-dependent molecular clutch between T cell signaling condensates and actin
    (eLife Sciences Publications, 2019-07-03) Ditlev, Jonathon ; Vega, Anthony R ; Köster, Darius Vasco ; Su, Xiaolei ; Tani, Tomomi ; Lakoduk, Ashley M ; Vale, Ronald D. ; Mayor, Satyajit ; Jaqaman, Khuloud ; Rosen, Michael K.
    During T cell activation, biomolecular condensates form at the immunological synapse (IS) through multivalency-driven phase separation of LAT, Grb2, Sos1, SLP-76, Nck, and WASP. These condensates move radially at the IS, traversing successive radially-oriented and concentric actin networks. To understand this movement, we biochemically reconstituted LAT condensates with actomyosin filaments. We found that basic regions of Nck and N-WASP/WASP promote association and co-movement of LAT condensates with actin, indicating conversion of weak individual affinities to high collective affinity upon phase separation. Condensates lacking these components were propelled differently, without strong actin adhesion. In cells, LAT condensates lost Nck as radial actin transitioned to the concentric network, and engineered condensates constitutively binding actin moved aberrantly. Our data show that Nck and WASP form a clutch between LAT condensates and actin in vitro and suggest that compositional changes may enable condensate movement by distinct actin networks in different regions of the IS. https://doi.org/10.7554/eLife.42695.001