RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis

Area of Science:

• Cell Biology
• Dermatology
• Molecular Biology

Background:

• Cilia-related proteins regulate diverse cellular functions.
• Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a known ciliary protein essential for ciliogenesis in epidermal keratinocytes.

Purpose of the Study:

• To investigate the role of RPGRIP1L in keratinocyte cell-cell adhesion and desmosome maintenance.
• To elucidate the mechanism underlying RPGRIP1L's function in epidermal integrity.

Main Methods:

• Genetic disruption of the Rpgrip1l gene in mice and HaCaT cells.
• Analysis of desmosomal protein expression, localization, and ultrastructure.
• In vivo and in vitro assays for cell-cell adhesion and endocytosis (AK23 labeling, biotinylation assays).
• Pharmacological inhibition of endocytosis using dynasore and sucrose.

Main Results:

• Genetic disruption of Rpgrip1l in mice led to intraepidermal blistering and compromised desmosome function.
• RPGRIP1L deficiency in HaCaT cells caused desmosomal protein mislocalization, independent of cilia.
• RPGRIP1L regulates desmoglein endocytosis, and its knockdown exacerbates endocytosis.
• Inhibition of endocytosis rescued the observed desmosomal defects.

Conclusions:

• RPGRIP1L plays a critical role in maintaining desmosomal junctions and epidermal integrity.
• RPGRIP1L possesses a cilia-independent function in regulating desmoglein endocytosis.
• This study identifies RPGRIP1L as a key regulator of the cellular endocytic pathway, impacting skin cell adhesion.