Proton-activated chloride channel PACC1 as acid sensor in epidermal desquamation.

Summary

This mechanistic study identifies PACC1 as the predominant proton sensor in keratinocytes, linking acidification to chloride efflux, JNK/AP-1 activation, KLK5/7 upregulation, and corneodesmosomal degradation. Genetic loss, pharmacologic inhibition, and rescue experiments converge to establish causality.

Key Findings

• PACC1 is the predominant acid-sensitive ion channel in keratinocytes.
• Proton-activated PACC1 triggers chloride efflux and JNK/AP-1 signaling, upregulating KLK5/7.
• Acid-induced KLK upregulation is abolished by PACC1 knockdown/knockout, proton-sensing–deficient mutants, and pharmacologic inhibition.
• Functional reconstitution of PACC1 restores the acid response and desquamation signaling.

Clinical Implications

While preclinical, targeting PACC1-JNK/AP-1-KLK signaling could enable precise control of exfoliation and barrier repair in disorders of desquamation and in cosmetic formulations for controlled peeling.

Limitations

• Preclinical mechanistic work without clinical or in vivo human validation reported in the abstract.
• Specificity and safety of PACC1 modulation in intact skin require further study.

Future Directions

Develop selective PACC1 modulators; test efficacy and safety in skin disease models and human explants; delineate structural basis of proton sensing for drug design.