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© The Rockefeller University Press, 0021-9525/1998//171 $5.00
The Journal of Cell Biology, Volume 140, Number 1, , 1998 171-182

Article

Ultraviolet Light Induces Apoptosis via Direct Activation of CD95 (Fas/APO-1) Independently of Its Ligand CD95L



Yoshinori Aragane, Dagmar Kulms, Dieter Metze, Gabriele Wilkes, Birgit Pöppelmann, Thomas A. Luger, and Thomas Schwarz

Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University of Münster, D-48149 Münster, Germany

Induction of apoptosis in keratinocytes by UV light is a critical event in photocarcinogenesis. Although p53 is of importance in this process, evidence exists that other pathways play a role as well. Therefore, we studied whether the apoptosis-related surface molecule CD95 (Fas/APO-1) is involved. The human keratinocyte cell line HaCaT expresses CD95 and undergoes apoptosis after treatment with UV light or with the ligand of CD95 (CD95L). Incubation with a neutralizing CD95 antibody completely prevented CD95L-induced apoptosis but not UV-induced apoptosis, initially suggesting that the CD95 pathway may not be involved. However, the protease CPP32, a downstream molecule of the CD95 pathway, was activated in UV-exposed HaCaT cells, and UV-induced apoptosis was blocked by the ICE protease inhibitor zVAD, implying that at least similar downstream events are involved in CD95- and UV-induced apoptosis. Activation of CD95 results in recruitment of the Fas-associated protein with death domain (FADD) that activates ICE proteases. Immunoprecipitation of UV-exposed HaCaT cells revealed that UV light also induces recruitment of FADD to CD95. Since neutralizing anti-CD95 antibodies failed to prevent UV-induced apoptosis, this suggested that UV light directly activates CD95 independently of the ligand CD95L. Confocal laser scanning microscopy showed that UV light induced clustering of CD95 in the same fashion as CD95L. Prevention of UV-induced CD95 clustering by irradiating cells at 10°C was associated with a significantly reduced death rate. Together, these data indicate that UV light directly stimulates CD95 and thereby activates the CD95 pathway to induce apoptosis independently of the natural ligand CD95L. These findings further support the concept that UV light can affect targets at the plasma membrane, thereby even inducing apoptosis.

Abbreviations used in this paper: CD95L, CD95 ligand; FADD, Fas- associated protein with death domain; ICE, interleukin-1β–converting enzyme; PARP, poly(ADP)ribose polymerase; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TRADD, TNFR1-associated death domain.

We gratefully thank K. Große-Heitmeyer, A. Mehling, and A. Schwarz for help and discussions, and we thank J. Bückmann and P. Wissel for preparing the graphs. The authors are grateful to Drs. P. Boukamp, N. Fusenig, V. Dixit, and D. Goeddel for providing reagents. The authors are thankful to Dr. T. Tezuka (Department of Dermatology, Kinki University School of Medicine, Osaka, Japan) for his continuous and generous support.


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