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Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated Cytotoxicity¹

Satoshi Jodo^2,*, Vyankatesh J. Pidiyar^2,, Sheng Xiao, Akira Furusaki^*, Rahul Sharma, Takao Koike^* and Shyr-Te Ju^3,

^* Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908

The cytotoxic function of CD178 (Fas ligand (FasL)) is critical to the maintenance of peripheral tolerance and immune-mediated tissue pathology. The active site of FasL resides at the FasL extracellular region (FasL_Ext) and it functions through binding/cross-linking Fas receptor on target cells. In this study, we report that FasL_Ext-mediated cytotoxicity is regulated by the FasL cytoplasmic tail (FasL_Cyt). Deleting the N-terminal 2–70 aa (70) or N-terminal 2–33 aa (33) reduced the cytotoxic strength as much as 30- to 100-fold. By contrast, change in the cytotoxic strength was not observed with FasL deleted of the proline-rich domains (45–74 aa, PRD) in the FasL_Cyt. Our study identifies a novel function of FasL_Cyt and demonstrates that FasL_2–33, a sequence unique to FasL, is critically required for the optimal expression of FasL_Ext-mediated cytotoxicity.

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