Fas ligand (CD178) cytoplasmic tail is a positive regulator of Fas ligand-mediated cytotoxicity.
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 (delta70) or N-terminal 2-33 aa (delta33) 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, delta 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.
Jodo
Satoshi
S
Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Pidiyar
Vyankatesh J
VJ
Xiao
Sheng
S
Furusaki
Akira
A
Sharma
Rahul
R
Koike
Takao
T
Ju
Shyr-Te
ST
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000235:genetics; D053222:Fas Ligand Protein; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D017384:Sequence Deletion
D018076:DNA, Complementary; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins