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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.

Titel:	A STAT3 palmitoylation cycle promotes T <subscript>H</subscript> 17 differentiation and colitis.
Autor/in / Beteiligte Person:	Zhang, M ; Zhou, L ; Xu, Y ; Yang, M ; Komaniecki, GP ; Kosciuk, T ; Chen, X ; Lu, X ; Zou, X ; Linder, ME ; Lin, H
Zeitschrift:	Nature, Jg. 586 (2020-10-01), Heft 7829, S. 434-439
Veröffentlichung:	Basingstoke : Nature Publishing Group ; <i>Original Publication</i>: London, Macmillan Journals ltd., 2020
Medientyp:	academicJournal
ISSN:	1476-4687 (electronic)
DOI:	10.1038/s41586-020-2799-2
Schlagwort:	Acetyltransferases deficiency Acetyltransferases genetics Acetyltransferases metabolism Acyltransferases antagonists & inhibitors Acyltransferases metabolism Animals Cell Membrane metabolism Cell Nucleus metabolism Colitis drug therapy Colitis metabolism Disease Models, Animal Female HEK293 Cells Humans Inflammatory Bowel Diseases metabolism Inflammatory Bowel Diseases pathology Male Mice Protein Transport Th17 Cells metabolism Thiolester Hydrolases antagonists & inhibitors Thiolester Hydrolases metabolism Up-Regulation Cell Differentiation Colitis immunology Colitis pathology Lipoylation STAT3 Transcription Factor chemistry STAT3 Transcription Factor metabolism Th17 Cells cytology Th17 Cells immunology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Nature] 2020 Oct; Vol. 586 (7829), pp. 434-439. <i>Date of Electronic Publication: </i>2020 Oct 07. MeSH Terms: Cell Differentiation* ; Lipoylation* ; Colitis / immunology ; Colitis / pathology ; STAT3 Transcription Factor / chemistry ; STAT3 Transcription Factor / metabolism ; Th17 Cells / cytology ; Th17 Cells / immunology ; Acetyltransferases / deficiency ; Acetyltransferases / genetics ; Acetyltransferases / metabolism ; Acyltransferases / antagonists & inhibitors ; Acyltransferases / metabolism ; Animals ; Cell Membrane / metabolism ; Cell Nucleus / metabolism ; Colitis / drug therapy ; Colitis / metabolism ; Disease Models, Animal ; Female ; HEK293 Cells ; Humans ; Inflammatory Bowel Diseases / metabolism ; Inflammatory Bowel Diseases / pathology ; Male ; Mice ; Protein Transport ; Th17 Cells / metabolism ; Thiolester Hydrolases / antagonists & inhibitors ; Thiolester Hydrolases / metabolism ; Up-Regulation References: Jiang, H. et al. Protein lipidation: occurrence, mechanisms, biological functions, and enabling technologies. Chem. Rev. 118, 919–988 (2018). 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Systematic screening for palmitoyl transferase activity of the DHHC protein family in mammalian cells. Methods 40, 177–182 (2006). (PMID: 10.1016/j.ymeth.2006.05.01517012030) Grant Information: R01 GM121540 United States GM NIGMS NIH HHS; United States HHMI Howard Hughes Medical Institute; S10 RR025502 United States RR NCRR NIH HHS; R01 DK107868 United States DK NIDDK NIH HHS; R35 GM131808 United States GM NIGMS NIH HHS Substance Nomenclature: 0 (STAT3 Transcription Factor) ; 0 (STAT3 protein, human) ; EC 2.3.- (Acyltransferases) ; EC 2.3.1.- (Acetyltransferases) ; EC 2.3.1.- (Dhhc7 protein, mouse) ; EC 2.3.1.- (ZDHHC7 protein, human) ; EC 3.1.2.- (LYPLA2 protein, human) ; EC 3.1.2.- (Lypla2 protein, mouse) ; EC 3.1.2.- (Thiolester Hydrolases) Entry Date(s): Date Created: 20201008 Date Completed: 20210114 Latest Revision: 20211008 Update Code: 20231215 PubMed Central ID: PMC7874492

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A STAT3 palmitoylation cycle promotes T <subscript>H</subscript> 17 differentiation and colitis.