Slowly getting a clue on CD95 ligand biology

Since the ligand for the death factor CD95 (CD95L) was identified almost a decade ago, it has been established that this molecule (CD95L, FasL, Apo-1L, CD178, TNFSF6, APT1LG1) has multiple immunoregulatory and pathophysiologically relevant functions. CD95L does not only act as a death factor when externalized with secretory lysosomes on cytotoxic T and NK cells or when expressed on CD4(+) T cells in the course of activation-induced cell death, it is also a key molecule for the establishment of immune privilege or tumor cell survival and may serve as a costimulatory molecule during T cell activation. Moreover, alterations of expression or shedding of different forms of CD95L are associated with many diseases including various malignancies, HIV infection, autoimmune disorders (systemic lupus erythematodes, rheumatoid arthritis), acute myocardial infarction, traumatic injury and many others. In most cases, however, the physiological link between altered CD95L expression and pathophysiology is unknown. Given the potency of the molecule to regulate death and survival of many different cell types, the control of CD95L production, transport, storage, shedding and release is of tremendous biological and clinical interest. This commentary aims at briefly summarizing the current knowledge, hypotheses and controversies about CD95L as a multifunctional ligand and receptor. It touches upon the complex networks of intracellular dynamics of protein transport and trafficking and the potential bidirectional signal transduction capacity of CD95L with a focus on molecular interactions that have been worked out over the past years.