DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11

• Main Authors: Loh Jia Tong, Teo, Joey Kay Hui, Kannan, Srinivasaraghavan, Verma, Chandra Shekhar, Andiappan, Anand Kumar, Lim, Hong-Hwa, Lam, Kong-Peng
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2024
• Subjects: Mathematical Sciences; Adaptor Proteins; Phosphoric Monoester Hydrolases
• Online Access: https://hdl.handle.net/10356/173519
• Institution: Nanyang Technological University

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.