期刊
CELL REPORTS
卷 33, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.108523
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资金
- BBSRC [BB/R007365/1]
- Versus Arthritis grant [20525]
- Human Frontier Science Program Organization
- Royal Society through HFSP fellowship [LT001463/2017-C]
- Wellcome Trust Investigator Award [WT25014/Z/16/Z]
- Royal Society through Dorothy Hodgkin fellowship [DHF\R1\191019]
- BBSRC [BB/R007365/1] Funding Source: UKRI
Elucidating the mechanisms that controlled T cell activation requires visualization of the spatial organization of multiple proteins on the submicron scale. Here, we use stoichiometrically accurate, multiplexed, single-molecule super-resolution microscopy (DNA-PAINT) to image the nanoscale spatial architecture of the primary inhibitor of the T cell signaling pathway, Csk, and two binding partners implicated in its membrane association, PAG and TRAF3. Combined with a newly developed co-clustering analysis framework, we find that Csk forms nanoscale clusters proximal to the plasma membrane that are lost post-stimulation and are re-recruited at later time points. Unexpectedly, these clusters do not co-localize with PAG at the membrane but instead provide a ready pool of monomers to downregulate signaling. By generating CRISPR-Cas9 knockout T cells, our data also identify that a major risk factor for autoimmune diseases, the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus, is essential for Csk nanocluster re-recruitment and for maintenance of the synaptic PAG population.
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