Insights into the molecular regulation of FasL (CD178) biology.
Fas ligand (FasL, CD95L, APO-1L, CD178, TNFSF6, APT1LG1) is the key death factor of receptor-triggered programmed cell death in immune cells. FasL/Fas-dependent apoptosis plays a pivotal role in activation-induced cell death, termination of immune responses, elimination of autoreactive cells, cytotoxic effector function of T and NK cells, and the establishment of immune privilege. Deregulation or functional impairment of FasL threatens the maintenance of immune homeostasis and defense and results in severe autoimmunity. In addition, FasL has been implicated as an accessory or costimulatory receptor in T cell activation. The molecular mechanisms underlying this reverse signaling capacity are, however, poorly understood and still controversially discussed. Many aspects of FasL biology have been ascribed to selective protein-protein interactions mediated by a unique polyproline region located in the membrane-proximal intracellular part of FasL. Over the past decade, we and others identified a large number of putative FasL-interacting molecules that bind to this polyproline stretch via Src homology 3 or WW domains. Individual interactions were analyzed in more detail and turned out to be crucial for the lysosomal storage, the transport and the surface appearance of the death factor and potentially also for reverse signaling. This review summarizes the work in the framework of the Collaborative Research Consortium 415 (CRC 415) and provides facts and hypotheses about FasL-interacting proteins and their potential role in FasL biology.
Christian-Albrechts-University, Institute of Immunology, D-24105 Kiel, Germany. lettau@immunologie.uni-kiel.de
Marcus
M
Lettau
Maren
M
Paulsen
Hendrik
H
Schmidt
Ottmar
O
Janssen
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D053222:Fas Ligand Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein