A STAT3 palmitoylation cycle promotes T_H17 differentiation and colitis

Area of Science:

• Molecular Biology
• Cellular Signaling
• Immunology

Background:

• Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification impacting protein function.
• The precise regulation of S-palmitoylation in specific biological processes remains largely unknown.
• STAT3 is a critical stimulator of T helper 17 (T_H17) cell differentiation.

Purpose of the Study:

• To investigate the role of S-palmitoylation in regulating STAT3 function and T_H17 cell differentiation.
• To identify the enzymes involved in the palmitoylation and depalmitoylation of STAT3.
• To explore the therapeutic potential of targeting this modification in inflammatory diseases like IBD.

Main Methods:

• Investigated STAT3 S-palmitoylation at cysteine 108.
• Identified DHHC7 as the palmitoyltransferase and acyl protein thioesterase 2 (APT2) as the depalmitoylase for STAT3.
• Utilized a mouse model of inflammatory bowel disease (IBD) to test therapeutic interventions.

Main Results:

• DHHC7-mediated palmitoylation of STAT3 promotes its membrane recruitment and phosphorylation.
• APT2-mediated depalmitoylation of p-STAT3 facilitates its nuclear translocation, enhancing T_H17 cell differentiation.
• Inhibition of APT2 or DHHC7 (via Zdhhc7 knockout) ameliorated IBD symptoms in a mouse model.

Conclusions:

• A STAT3 palmitoylation-depalmitoylation cycle critically regulates T_H17 cell differentiation.
• Targeting DHHC7 or APT2 represents a potential therapeutic strategy for inflammatory bowel disease.
• This study provides a model for how S-palmitoylation regulates cell signaling pathways.