Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells

• DOI: 10.1084/jem.20240272
• Publication Date: 2025-03-20T13:44:11Z
• Authors: Bradly M. Bauman; Jeffrey R. Stinson; Melissa A. Kallar...; Lei Haley Huang; Andrew M. Frank; Gauthaman Sukumar; Nermina Saucier; Clifton L. Dalgard; Alice Y. Chan; Joshua D. Milner; Megan A. Cooper; Andrew L. Snow
• Keywords: Expression (computer science)

Several "primary atopic disorders" are linked to monogenic defects that attenuate TCR signaling, favoring T helper type 2 (TH2) cell differentiation. Patients with CARD11-associated atopy dominant interference of NF-κB signaling (CADINS) disease suffer from severe atopy, caused by germline loss-of-function/dominant interfering (LOF/DI) CARD11 variants. The scaffold enables TCR-induced activation NF-κB, mTORC1, and JNK yet the function CARD11-dependent in cells remains nebulous. Here we show is critical for JNK1 JNK2, as well canonical JUN/FOS AP-1 family members. Patient-derived DI variants attenuated WT mirroring effects on NF-κB. Transcriptome profiling revealed inhibition upregulated expression GATA3 NFATC1, key transcription factors TH2 development. Further, impaired CARD11-JNK was enhanced CADINS patient cells. Our findings reveal a novel intrinsic mechanism connecting GATA3/NFAT2 induction differentiation patients.