Novel negative regulator of expression in Fas ligand (CD178) cytoplasmic tail: evidence for translational regulation and against Fas ligand retention in secretory lysosomes.
Fas ligand ((FasL) CD178), a type II transmembrane protein, induces apoptosis of cells expressing the Fas receptor. It possesses a unique cytoplasmic tail (FasLCyt) of 80 aa. As a type II transmembrane protein, the early synthesis of FasLCyt 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 FasLCyt (FasLPRD) inhibits FasL membrane expression by retaining FasL in the secretory lysosomes. This report shows that deletion of aa 2-33 of FasLCyt dramatically increased total FasL levels and FasL cell surface expression. This negative regulator of FasL expression is dominant despite the presence of FasLPRD. In addition, retention of proline-rich domain-containing FasL in the cytoplasm was not observed. Moreover, we demonstrated that FasLCyt 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 FasLCyt region and its mechanism of action.
Department of Internal Medicine, Division of Rheumatology and Immunology, University of Virginia, Charlottesville 22908, USA.
Sheng
S
Xiao
Umesh S
US
Deshmukh
Satoshi
S
Jodo
Takao
T
Koike
Rahul
R
Sharma
Akiro
A
Furusaki
Sun-sang J
SS
Sung
Shyr-Te
ST
Ju
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D003593:Cytoplasm / Q000378:metabolism*; D053222:Fas Ligand Protein; D008247:Lysosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D014176:Protein Biosynthesis; D051381:Rats
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins