Loss of ceramide synthase 3 causes lethal skin barrier disruption.
The stratum corneum as the outermost epidermal layer protects against exsiccation and infection. Both the underlying cornified envelope (CE) and the intercellular lipid matrix contribute essentially to these two main protective barriers. Epidermis-unique ceramides with ultra-long-chain acyl moities (ULC-Cers) are key components of extracellular lipid lamellae (ELL) and are bound to CE proteins, thereby contributing to the cornified lipid envelope (CLE). Here, we identified human and mouse ceramide synthase 3 (CerS3), among CerS1-6, to be exclusively required for the ULC-Cer synthesis in vitro and of mouse CerS3 in vivo. Deficiency of CerS3 in mice results in complete loss of ULC-Cers (≥C26), lack of continuous ELL and a non-functional CLE. Consequently, newborn mutant mice die shortly after birth from transepidermal water loss. Mutant skin is prone to Candida albicans infection highlighting ULC-Cers to be pivotal for both barrier functions. Persistent periderm, hyperkeratosis and deficient cornification are hallmarks of mutant skin demonstrating loss of Cers to trigger a keratinocyte maturation arrest at an embryonic pre-barrier stage.
Cellular & Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany.
Richard
R
Jennemann
Mariona
M
Rabionet
Karin
K
Gorgas
Sharon
S
Epstein
Alexander
A
Dalpke
Ulrike
U
Rothermel
Aline
A
Bayerle
Franciscus
F
van der Hoeven
Silke
S
Imgrund
Joachim
J
Kirsch
Walter
W
Nickel
Klaus
K
Willecke
Howard
H
Riezman
Hermann-Josef
HJ
Gröne
Roger
R
Sandhoff
D000818:Animals; D000831:Animals, Newborn; D002176:Candida albicans / Q000502:physiology; D002462:Cell Membrane / Q000648:ultrastructure; D002518:Ceramides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000201:enzymology; D005227:Fatty Acids / Q000378:metabolism; D005804:Genes, Lethal; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D012867:Skin / Q000382:microbiology; D012879:Skin Physiological Phenomena; D051049:Sphingosine N-Acyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014870:Water Loss, Insensible
D002518:Ceramides; D005227:Fatty Acids; C513562:CerS3 protein, mouse; D051049:Sphingosine N-Acyltransferase