# ZDHHC14-Mediated TEAD4 Palmitoylation Drives Th17 Cell Recruitment in Renal Immunopathology

## TL;DR

This study shows how a protein modification called palmitoylation helps Th17 cells invade the kidneys in a type of kidney disease, offering a new way to slow the disease.

## Contribution

The study identifies TEAD4 palmitoylation as a novel regulatory mechanism driving Th17 cell recruitment in IgA nephropathy.

## Key findings

- TEAD4 activity is regulated by palmitoylation, not protein expression levels, in IgA nephropathy.
- ZDHHC14 is the key enzyme mediating TEAD4 palmitoylation in renal tissues.
- Inhibiting ZDHHC14 reduces Th17 cell infiltration and delays disease progression in mouse models.

## Abstract

Palmitoylation, a crucial posttranslational protein modification, plays an undefined role in immune-mediated kidney diseases. This study reveals a novel mechanism whereby palmitoylation regulates the activity of transcription factor TEAD4 to facilitate T helper 17 (Th17) cell recruitment in IgA nephropathy (IgAN), suggesting that inhibition of palmitoylation could serve as a “brake” mechanism to impede disease progression. By analyzing samples from IgAN patients and mouse models, we identified a marked positive correlation between the extent of Th17 cell infiltration in renal tissues and disease severity. Mechanistically, under inflammatory conditions, injured tubular epithelial cells up-regulate CCL20 expression through the transcription factor TEAD4, thereby facilitating Th17 cell recruitment. Notably, TEAD4 activity is regulated by palmitoylation modification rather than changes in protein expression levels. Further analysis identified ZDHHC14 as the key palmitoyltransferase mediating TEAD4 palmitoylation, which is highly expressed in renal tissues of both IgAN patients and model mice. Knockdown of ZDHHC14 effectively reduced CCL20 expression and subsequent Th17 cell infiltration. In vivo therapeutic experiments demonstrated that administration of the ZDHHC inhibitor 2-BP effectively attenuated Th17 cell infiltration and renal interstitial fibrosis in model mice, markedly delaying disease progression. This study provides the first evidence of TEAD4 palmitoylation-mediated regulation in immune-mediated kidney and proposes a novel strategy to modulate Th17-driven disorders, with broad implications for autoimmune and fibrotic diseases.