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Novel Negative Regulator of Expression in Fas Ligand (CD178) Cytoplasmic Tail: Evidence for Translational Regulation and against Fas Ligand Retention in Secretory Lysosomes¹

Sheng Xiao^*, Umesh S. Deshmukh^*, Satoshi Jodo, Takao Koike, Rahul Sharma^*, Akiro Furusaki, Sun-sang J. Sung^* and Shyr-Te Ju^2,*

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

Fas ligand ((FasL) CD178), a type II transmembrane protein, induces apoptosis of cells expressing the Fas receptor. It possesses a unique cytoplasmic tail (FasL_Cyt) of 80 aa. As a type II transmembrane protein, the early synthesis of FasL_Cyt could affect FasL translation by impacting FasL endoplasmic reticulum translocation and/or endoplasmic reticulum retention. Previous studies suggest that the proline-rich domain (aa 43–70) in FasL_Cyt (FasL_PRD) inhibits FasL membrane expression by retaining FasL in the secretory lysosomes. This report shows that deletion of aa 2–33 of FasL_Cyt dramatically increased total FasL levels and FasL cell surface expression. This negative regulator of FasL expression is dominant despite the presence of FasL_PRD. In addition, retention of proline-rich domain-containing FasL in the cytoplasm was not observed. Moreover, we demonstrated that FasL_Cyt regulates FasL expression by controlling the rate of de novo synthesis of FasL. Our study demonstrated a novel negative regulator of FasL expression in the FasL_Cyt region and its mechanism of action.

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