Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis.
Epidermal keratinocytes form a structural and immune barrier that is essential for skin homeostasis. However, the mechanisms that regulate epidermal barrier function are incompletely understood. Here we have found that keratinocyte-specific deletion of the gene encoding RAB guanine nucleotide exchange factor 1 (RABGEF1, also known as RABEX-5) severely impairs epidermal barrier function in mice and induces an allergic cutaneous and systemic phenotype. RABGEF1-deficient keratinocytes exhibited aberrant activation of the intrinsic IL-1R/MYD88/NF-κB signaling pathway and MYD88-dependent abnormalities in expression of structural proteins that contribute to skin barrier function. Moreover, ablation of MYD88 signaling in RABGEF1-deficient keratinocytes or deletion of Il1r1 restored skin homeostasis and prevented development of skin inflammation. We further demonstrated that epidermal RABGEF1 expression is reduced in skin lesions of humans diagnosed with either atopic dermatitis or allergic contact dermatitis as well as in an inducible mouse model of allergic dermatitis. Our findings reveal a key role for RABGEF1 in dampening keratinocyte-intrinsic MYD88 signaling and sustaining epidermal barrier function in mice, and suggest that dysregulation of RABGEF1 expression may contribute to epidermal barrier dysfunction in allergic skin disorders in mice and humans. Thus, RABGEF1-mediated regulation of IL-1R/MYD88 signaling might represent a potential therapeutic target.
Thomas
T
Marichal
Nicolas
N
Gaudenzio
Sophie
S
El Abbas
Riccardo
R
Sibilano
Oliwia
O
Zurek
Philipp
P
Starkl
Laurent L
LL
Reber
Dimitri
D
Pirottin
Jinah
J
Kim
Pierre
P
Chambon
Axel
A
Roers
Nadine
N
Antoine
Yuko
Y
Kawakami
Toshiaki
T
Kawakami
Fabrice
F
Bureau
See-Ying
SY
Tam
Mindy
M
Tsai
Stephen J
SJ
Galli
D000818:Animals; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004817:Epidermis / Q000473:pathology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D020662:Guanine Nucleotide Exchange Factors; C583355:IL1R1 protein, mouse; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C108382:RABGEF1 protein, human; C510870:RabGEF1 protein, mouse; D053573:Receptors, Interleukin-1 Type I