Editors' ChoiceImmunology

Palmitoylation and colitis

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Science Signaling  20 Oct 2020:
Vol. 13, Issue 654, eabf2918
DOI: 10.1126/scisignal.abf2918

Interrupting the palmitoylation-depalmitoylation cycle of the transcriptional regulator STAT3 relieves IBD symptoms in mice.

Inflammatory bowel disease (IBD) is associated with the increased differentiation of naïve CD4+ T cells into proinflammatory T helper 17 (TH17) cells. The transcriptional regulator STAT3 promotes the generation of TH17 cells. STAT3 is activated by phosphorylation by the kinase JAK2 at the plasma membrane and then translocates to the nucleus. Noting the importance of the posttranslational modification S-palmitoylation in protein-membrane associations, Zhang et al. showed that STAT3 was palmitoylated in HEK293T cells and mouse splenocytes by the palmitoyltransferase DHHC7 at Cys108, which enhanced the plasma membrane recruitment of STAT3. Knockdown of DHHC7 decreased the abundance of STAT3 at plasma membranes but increased its nuclear localization. STAT3 palmitoylation by DHHC7 enhanced its phosphorylation and activation by JAK2. Although acyl protein thioesterases (APTs) remove palmitoyl groups from proteins, knockdown of APT2 unexpectedly inhibited the transcriptional activity and nuclear localization of STAT3. Further experiments showed that APT2 preferentially enhanced the depalmitoylation and nuclear translocation of phosphorylated STAT3 (pSTAT3) compared to unphosphorylated STAT3. Expression of DHHC7 increased the number of TH17 cells generated from mouse splenocytes, whereas inhibition of APT2 had the opposite effect. In a mouse model of IBD, targeting DHHC7 or APT2 decreased the number of TH17 cells and reduced disease severity. Compared to healthy donors, patients with IBD had increased expression of the genes encoding DHHC7 and APT2 in peripheral blood mononuclear cells. The authors propose a model by which DHHC7 palmitoylates STAT3, leading to its recruitment to the plasma membrane where it is phosphorylated and activated by JAK2. APT2 then depalmitoylates pSTAT3, increasing its nuclear localization and activity. These data suggest that targeting this posttranslational modification cycle might alleviate symptoms in diseases driven by proinflammatory TH17 cells.

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