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Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice
D Kreder1, O Krut, S Adam-Klages
1Institute of Immunology, University of Kiel, Brunswiker Strasse 4, 24105 Kiel, Germany.
Abstract:
The WD-40 repeat protein FAN binds to a distinct domain of the p55 receptor for tumor necrosis factor (TNF) and signals the activation of neutral sphingomyelinase (N-SMase). To analyze the physiological role of FAN in vivo, we generated FAN-deficient mice by targeted gene disruption. Mice lacking a functional FAN protein do not show any overt phenotypic abnormalities; in particular, the architecture and cellular composition of lymphoid organs appeared to be unaltered. An essential role of FAN in the TNF-induced activation of N-SMase was demonstrated using thymocytes from FAN knockout mice. Activation of extracellular signal-regulated kinases in response to TNF treatment, however, was not impaired by the absence of the FAN protein. FAN-deficient mice show delayed kinetics of recovery after cutaneous barrier disruption suggesting a physiological role of FAN in epidermal barrier repair. Although FAN exhibits striking structural homologies with the CHS/Beige proteins, FAN-deficient mice did not reproduce the phenotype of beige mice.
Insights
The WD-40 repeat protein FAN is crucial for TNF-induced N-SMase activation. FAN-deficient mice show delayed skin barrier repair, indicating its role in epidermal repair.
Area of Science:
- Immunology
- Cell Biology
- Dermatology
Background:
- The WD-40 repeat protein FAN interacts with the p55 receptor for tumor necrosis factor (TNF).
- FAN signaling activates neutral sphingomyelinase (N-SMase).
Purpose of the Study:
- To investigate the in vivo physiological role of FAN.
- To determine FAN's function in TNF signaling and epidermal repair.
Main Methods:
- Generation of FAN-deficient mice via targeted gene disruption.
- Analysis of lymphoid organ architecture and cellularity.
- Assessment of TNF-induced N-SMase activation in thymocytes.
- Evaluation of extracellular signal-regulated kinase activation.
- Study of cutaneous barrier repair kinetics.
Main Results:
- FAN knockout mice exhibited no overt phenotypic abnormalities or alterations in lymphoid organs.
- FAN is essential for TNF-induced N-SMase activation in thymocytes.
- Extracellular signal-regulated kinase activation by TNF was not impaired in FAN-deficient mice.
- FAN-deficient mice displayed delayed recovery kinetics after skin barrier disruption.
- FAN deficiency did not replicate the phenotype observed in beige mice, despite structural similarities.
Conclusions:
- FAN plays a critical role in TNF-mediated N-SMase activation.
- FAN is implicated in epidermal barrier repair processes.
- The absence of FAN does not affect TNF-induced ERK activation or lymphoid organ homeostasis.
- FAN's function differs from that of CHS/Beige proteins.