SMAD2 S-palmitoylation promotes its linker region phosphorylation and T_H17 cell differentiation in a mouse model of...

The transcriptional regulators SMAD2 and SMAD3 share the same primary signaling pathway in response to the cytokine TGFβ. However, whereas SMAD2 stimulates the differentiation of naive CD4⁺ T cells into proinflammatory T helper 17 cells (T_H17 cells), SMAD3 stimulates the differentiation of anti-inflammatory regulatory T cells (T_reg cells). Here, we report a dynamic SMAD2-specific posttranslational modification important for T_H17 cell differentiation. SMAD2, but not SMAD3, was reversibly S-palmitoylated at cysteine-41 and cysteine-81 by the palmitoyltransferase DHHC7 and depalmitoylated by the acyl protein thioesterase APT2. As a result, SMAD2 was recruited to intracellular membranes where its linker region was phosphorylated, leading to its interaction with the transcriptional regulator STAT3. Nuclear translocation of the SMAD2-STAT3 complex induced the expression of their target genes that promoted T_H17 cell differentiation. Perturbation of SMAD2-STAT3 binding by inhibiting the palmitoylation-depalmitoylation cycle suppressed T_H17 cell differentiation and reduced disease severity in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Thus, the S-palmitoylation-depalmitoylation cycle mediated by DHHC7 and APT2 specifically regulates SMAD2, providing insights into the functional differences between SMAD2 and SMAD3 and the distinct role of SMAD2 in T_H17 cell differentiation. The findings further highlight DHHC7 and APT2 as potential therapeutic targets for the treatment of T_H17 cell-mediated inflammatory diseases, including MS.