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Title: DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11
Authors: Loh Jia Tong
Teo, Joey Kay Hui
Kannan, Srinivasaraghavan
Verma, Chandra Shekhar
Andiappan, Anand Kumar
Lim, Hong-Hwa
Lam, Kong-Peng
Keywords: Mathematical Sciences
Issue Date: 2023
Source: Loh Jia Tong, Teo, J. K. H., Kannan, S., Verma, C. S., Andiappan, A. K., Lim, H. & Lam, K. (2023). DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11. Science Signaling, 16(809), eadg5171-.
Project: MRC/OFIRG19may-0083
Journal: Science Signaling
Abstract: The scaffolding protein CARD11 is a critical mediator of antigen receptor signaling in lymphocytes. Hypomorphic (partial loss-of-function) mutations in CARD11 are associated with the development of severe atopic dermatitis, in which T cell receptor signaling is reduced and helper T cell differentiation is skewed to an allergy-associated type 2 phenotype. Here, we found that the docking protein DOK3 plays a key role in the pathogenesis of atopic dermatitis by suppressing CARD11 activity. DOK3 interacted with CARD11 and decreased its phosphorylation in T cells by recruiting the catalytic subunit of protein phosphatase 4, thereby dampening downstream signaling. Knocking out Dok3 enhanced the production of the cytokine IFN-γ by T cells, which conferred protection against experimental atopic dermatitis-like skin inflammation in mice. The expression of DOK3 was increased in T cells isolated from patients with atopic dermatitis and inversely correlated with IFNG expression. A subset of hypomorphic CARD11 variants found in patients with atopic dermatitis bound more strongly than wild-type CARD11 to DOK3. Our findings suggest that the strength of the interaction of DOK3 with CARD11 may predispose individuals to developing atopic dermatitis.
ISSN: 1945-0877
DOI: 10.1126/scisignal.adg5171
Schools: School of Biological Sciences 
Rights: © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

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