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.
Xiao
Sheng
S
Department of Internal Medicine, Division of Rheumatology and Immunology, University of Virginia, Charlottesville 22908, USA.
Deshmukh
Umesh S
US
Jodo
Satoshi
S
Koike
Takao
T
Sharma
Rahul
R
Furusaki
Akiro
A
Sung
Sun-sang J
SS
Ju
Shyr-Te
ST
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