Palmitoylation of TRIM47 Regulates ATG16L1-Mediated Autophagy to Exacerbate Respiratory Distress Syndrome in Sepsis.

Summary

Using CLP and LPS ARDS models, the authors show that ZDHHC21-mediated palmitoylation of TRIM47 at C520 promotes ATG16L1 ubiquitination, suppresses autophagy (reduced LC3B, fewer autophagosomes), and worsens lung injury. TRIM47 knockdown restored ATG16L1 and autophagy, implicating a druggable palmitoylation–autophagy axis in sepsis-induced ARDS.

Key Findings

• TRIM47 palmitoylation increased in CLP and LPS models of sepsis-induced ARDS, coinciding with reduced autophagy (lower LC3B, fewer autophagosomes).
• Site-specific palmitoylation at C520 on TRIM47 inhibited autophagy and exacerbated lung injury.
• TRIM47 knockdown upregulated ATG16L1, while TRIM47 palmitoylation promoted ATG16L1 ubiquitination.
• ZDHHC21 bound TRIM47 and enhanced its palmitoylation, thereby suppressing autophagy in sepsis-induced ARDS.

Clinical Implications

Modulating palmitoylation (e.g., targeting ZDHHC21 or TRIM47 palmitoylation) could restore autophagy and mitigate lung injury in sepsis-induced ARDS; ATG16L1 ubiquitination may serve as a biomarker.

Limitations

• Preclinical models without human tissue validation or clinical outcomes
• No pharmacologic inhibition/activation experiments to test therapeutic reversibility in vivo

Future Directions

Validate the ZDHHC21–TRIM47–ATG16L1 axis in human sepsis-ARDS specimens; test palmitoylation inhibitors or genetic modulation for therapeutic benefit; explore biomarker utility of ATG16L1 ubiquitination.