A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis

Mingming Zhang, Lixing Zhou, Yuejie Xu, Min Yang, Yilai Xu, Garrison Paul Komaniecki, Tatsiana Kosciuk, Xiao Chen, Xuan Lu, Xiaoping Zou, Maurine E. Linder and Hening Lin ()
Additional contact information
Mingming Zhang: Cornell University
Lixing Zhou: Sichuan University
Yuejie Xu: Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University and Nanjing Medical University
Min Yang: Cornell University
Yilai Xu: Cornell University
Garrison Paul Komaniecki: Cornell University
Tatsiana Kosciuk: Cornell University
Xiao Chen: Cornell University
Xuan Lu: Cornell University
Xiaoping Zou: Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University and Nanjing Medical University
Maurine E. Linder: Cornell University
Hening Lin: Cornell University

Nature, 2020, vol. 586, issue 7829, 434-439

Abstract: Abstract 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 thioesterases1,2. 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 (TH17) cell differentiation stimulator, STAT33,4, 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 TH17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects TH17 cell differentiation. Overactivation of TH17 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.

Date: 2020
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DOI: 10.1038/s41586-020-2799-2

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