Differential protein-protein interactions underlie signaling mediated by the TCR and a 4-1BB domain-containing CAR.

Autor:	Ritmeester-Loy SA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA., Draper IH; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA., Bueter EC; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA., Lautz JD; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA., Zhang-Wong Y; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA., Gustafson JA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.; Seattle Children's Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA., Wilson AL; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.; Seattle Children's Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA., Lin C; Proteomics and Metabolomics Facility, Fred Hutchinson Cancer Center, Seattle, WA 98101, USA., Gafken PR; Proteomics and Metabolomics Facility, Fred Hutchinson Cancer Center, Seattle, WA 98101, USA., Jensen MC; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.; Seattle Children's Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.; Department of Pediatrics, University of Washington, Seattle, WA 98101, USA., Orentas R; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.; Department of Pediatrics, University of Washington, Seattle, WA 98101, USA., Smith SEP; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.; Department of Pediatrics, University of Washington, Seattle, WA 98101, USA.; Graduate Program in Neuroscience, University of Washington, Seattle, WA 98101, USA.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2024 Mar 05; Vol. 17 (826), pp. eadd4671. Date of Electronic Publication: 2024 Mar 05.
DOI:	10.1126/scisignal.add4671
Abstrakt:	Cells rely on activity-dependent protein-protein interactions to convey biological signals. For chimeric antigen receptor (CAR) T cells containing a 4-1BB costimulatory domain, receptor engagement is thought to stimulate the formation of protein complexes similar to those stimulated by T cell receptor (TCR)-mediated signaling, but the number and type of protein interaction-mediating binding domains differ between CARs and TCRs. Here, we performed coimmunoprecipitation mass spectrometry analysis of a second-generation, CD19-directed 4-1BB:ζ CAR (referred to as bbζCAR) and identified 128 proteins that increased their coassociation after target engagement. We compared activity-induced TCR and CAR signalosomes by quantitative multiplex coimmunoprecipitation and showed that bbζCAR engagement led to the activation of two modules of protein interactions, one similar to TCR signaling that was more weakly engaged by bbζCAR as compared with the TCR and one composed of TRAF signaling complexes that was not engaged by the TCR. Batch-to-batch and interindividual variations in production of the cytokine IL-2 correlated with differences in the magnitude of protein network activation. Future CAR T cell manufacturing protocols could measure, and eventually control, biological variation by monitoring these signalosome activation markers.
Databáze:	MEDLINE
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