A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis

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 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 the 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 [Author:OK?]-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, †

S-Palmitoylation-Dependent Regulation of Cardiomyocyte Rac1 Signaling Activity and Cardiac Hypertrophy

“…S-palmitoylation plays critical roles in the pathophysiology of cancer [45][46][47][48][49]85 , inflammation [50][51][52][53] , peripheral artery disease 86 , and thrombosis 87 , yet no direct role has been established for this post-translational modification in the pathogenesis of cardiac hypertrophy and heart failure. Indeed, despite S-palmitoylation of essential cardiac signal transducing proteins (i.e.…”

“…GTPases and G-protein a subunits, can undergo inducible S-palmitoylation to facilitate translocation to select membrane domains where they associate with receptors and activate signaling effectors followed by depalmitoylation and S-palmitoylation again by Golgi-localized zDHHC enzymes. This results in successive rounds of membrane translocation and sustained signaling output in a process termed palmitoylation cycling 31,32,50,106,107 . For example, N-Ras is S-palmitoylated at the Golgi by zDHHC9 and depalmitoylated at the plasma membrane by ABHD17 family thioesterases to dynamically regulate N-Ras signaling activity.…”

“…Consequently, loss of zDHHC9 or inhibition of ABHD17 enzymes impairs growth and proliferation of N-Ras-dependent cancer cells 16,85,[107][108][109] . Similarly, STAT3 is S-palmitoylated by zDHHC7 at the Golgi to induce its association with growth factor receptors and phosphorylation at the membrane where it is then depalmitoylated by APT-2 to enable nuclear translocation and activation of an inflammatory gene expression program 50 . Disruption of STAT3 S-palmitoylation cycling by genetic deletion of zDHHC7 or pharmacological inhibition of APT-2 ameliorates inflammatory gene expression and colitis in an animal model inflammatory bowel disease 50 .…”

“…Similarly, STAT3 is S-palmitoylated by zDHHC7 at the Golgi to induce its association with growth factor receptors and phosphorylation at the membrane where it is then depalmitoylated by APT-2 to enable nuclear translocation and activation of an inflammatory gene expression program 50 . Disruption of STAT3 S-palmitoylation cycling by genetic deletion of zDHHC7 or pharmacological inhibition of APT-2 ameliorates inflammatory gene expression and colitis in an animal model inflammatory bowel disease 50 . Thus, palmitoylation cycling of soluble signaling proteins can provide a regulatory mechanism to garner sustained signaling and activation of downstream transduction circuitry.…”

Protein cysteine palmitoylation in immunity and inflammation

“…The site of palmitoylation is not identified, but it appears that the knockdown of ZDHHC5 and ZDHHC8 affects IL6ST surface localization and the downstream STAT3 phosphorylation [51]. Interestingly, STAT3 itself is regulated by a palmitoylation-depalmitoylation cycle (Figure 3B) [52]. ZDHHC7 and, to a smaller extent, ZDHHC3, palmitoylate STAT3 on Cys108, promoting its plasma membrane localization, where IL6ST and JAK2 are localized, thus facilitating STAT3 phosphorylation.…”