A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis

• Published in: Nature (London) Vol. 586; no. 7829; pp. 434 - 439
• Main Authors: Zhang, Mingming, Zhou, Lixing, Xu, Yuejie, Yang, Min, Xu, Yilai, Komaniecki, Garrison Paul, Kosciuk, Tatsiana, Chen, Xiao, Lu, Xuan, Zou, Xiaoping, Linder, Maurine E., Lin, Hening
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.10.2020; Nature Publishing Group
• Subjects: 14/19; 14/35; 38; 38/109; 38/70; 38/77; 631/250/256; 631/45/607/1172; 631/80/86; 631/92/458; 82; 82/29; 82/80; 96; Cell activation; Cell differentiation; Colitis; Cysteine; Differentiation (biology); Disease; Helper cells; Humanities and Social Sciences; Inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Kinases; Lymphocytes T; multidisciplinary; Nuclei (cytology); Palmitoylation; Perturbation; Phosphorylation; Plasma; Post-translation; Proteins; Recruitment; Science; Science (multidisciplinary); Signaling; Signs and symptoms; Stat3 protein; Stimulators; Thioesterase
• DOI: 10.1038/s41586-020-2799-2
• ISSN: 0028-0836; 1476-4687

Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein thioesterases 1 , 2 . Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (T H 17) cell differentiation stimulator, STAT3 3 , 4 , is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation–depalmitoylation cycle enhances STAT3 activation and promotes T H 17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects T H 17 cell differentiation. Overactivation of T H 17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout of Zdhhc7 —which encodes DHHC7—relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events. The dynamic and reversible S-palmitoylation of the transcription factor STAT3 enhances its activation and promotes the differentiation of T H 17 cells.