Rescue of sirtuin inhibitor-dependent decrease in claudin-4 expression and paracellular barrier property in...

Area of Science:

• Dermatology
• Cell Biology
• Biochemistry

Background:

• Skin barrier function is crucial for protection and is maintained by tight junction proteins like claudin-1 (CLDN1) and claudin-4 (CLDN4).
• Sirtuin-2 (SIRT2) activity declines with age in keratinocytes, compromising CLDN4 expression and skin barrier integrity.

Purpose of the Study:

• To investigate the role of SIRT2 in regulating CLDN4 expression and skin barrier function.
• To evaluate the potential of SIRT2 activators, such as epigallocatechin gallate (EGCG), in counteracting age-related barrier dysfunction.

Main Methods:

• Utilized in vitro SIRT2 activity assays and human keratinocyte-derived HaCaT cells.
• Administered Tenovin-1 (Ten-1), a SIRT2 inhibitor, and EGCG or green tea extract (GT) to assess effects on CLDN4 expression, localization, and acetylation.
• Measured transepithelial electrical resistance and paracellular permeability using FD4 as a flux marker.

Main Results:

• Ten-1 decreased SIRT2 activity, CLDN4 protein levels, tight junction localization of CLDN4, and increased CLDN4 acetylation at K196.
• EGCG and GT rescued SIRT2 activity and reversed the Ten-1-induced decrease in CLDN4 expression and barrier function.
• Ten-1 affected CLDN4 expression via K196 acetylation, while CLDN1 expression remained unaffected by Ten-1 or EGCG.

Conclusions:

• SIRT2 plays a key role in maintaining skin barrier function by regulating CLDN4 expression and localization.
• EGCG demonstrates potential as a therapeutic agent to enhance skin barrier function and mitigate aging-induced decline by activating SIRT2 and inhibiting CLDN4 acetylation.