A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis
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...
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| Vydané v: | Nature (London) Ročník 586; číslo 7829; s. 434 - 439 |
|---|---|
| Hlavní autori: | , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
London
Nature Publishing Group UK
15.10.2020
Nature Publishing Group |
| Predmet: | |
| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
| On-line prístup: | Získať plný text |
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| Shrnutí: | 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. |
|---|---|
| Bibliografia: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions M.Z. and H.L. designed the study; M.Z. carried out the cell experiments and the protein analysis; M.Z. and X.C. performed the click chemistry analysis; L.Z. [Author: Please clarify which author this refers to, as there seems to be no one with these initials in the author list. Should this be L.Z.?] and Yuejie Xu collected the human samples and performed the analyses; M.Y. carried out the chemical synthesis; Yilai Xu [Author: Is this Yilai Xu?], G.P.K. and T.K. repeated key cellular biochemical experiments with both DHHC7 and APT2; X.L. and M.Z. carried out the mouse experiments; M.Z. [Author: Please clarify which author this refers to; should this be M.Z.?] and H.L. drafted the manuscript with inputs from all authors; X.Z. directed the patient study; M.E.L. provided all of the DHHC plasmids and participated in data analysis; and H.L. directed the biochemical studies. All authors read and approved the final manuscript. |
| ISSN: | 0028-0836 1476-4687 1476-4687 |
| DOI: | 10.1038/s41586-020-2799-2 |