title: Regulation of FasL expression: a SH3 domain containing protein family involved in the lysosomal association of FasL.
abstract: As a death factor of T cells and Natural Killer (NK) cells, Fas Ligand (FasL) is stored in association with secretory lysosomes. Upon stimulation, these cytotoxic granules are transported to the cell membrane where FasL is exposed on the cell surface, shed or secreted. It has been noted before that the proline-rich domain within the cytosolic part of FasL is required for its vesicular association. However, the molecular interactions involved in targeting FasL to secretory lysosomes or to the plasma membrane have not been elucidated. We now identified a family of structurally related proteins that upon co-expression with FasL reallocate the death factor from a membrane to an intracellular localization. Members of this protein family are characterized by a similar domain structure and include FBP17, PACSIN1-3, CD2BP1, CIP4, Rho-GAP C1 and several hypothetical proteins. We show that all tested members of this "FCH/SH3-family" co-precipitate FasL from transfectants. The interactions strictly depend on functional SH3 domains within the FCH/SH3 proteins. Since co-expression of FasL with individual FCH/SH3 proteins dramatically alters the intracellular localization of FasL especially in non-hematopoietic cells, our data suggest that FCH/SH3 proteins might play an important role for the subcellular distribution and lysosomal association of FasL.
authors.affiliation: Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Michaelisstr. 5, D-24105 Kiel, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.forename: Wenbin
authors.initials: W
authors.lastname: Chen
authors.forename: Marcus
authors.initials: M
authors.lastname: Lettau
authors.forename: Graziella
authors.initials: G
authors.lastname: Podda
authors.forename: Martin
authors.initials: M
authors.lastname: Zörnig
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Ottmar
authors.initials: O
authors.lastname: Janssen
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D053222:Fas Ligand Protein; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D015603:Keratinocytes / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D002402:Cathepsin D