Disruption of fas-fas ligand signaling, apoptosis, and innate immunity by bacterial pathogens.

Fas ligand (FasL, CD95L) is a type-II membrane protein withinthe tumor necrosis factor (TNF) superfamily of death receptors [1].FasL shares 25%–30% sequence homology with related familymember proteins such as tumor necrosis factor alpha (TNFa) andTNF-related apoptosis-inducing ligand (TRAIL), with the mostsimilarity present in the C-terminal homology ectodomain thatextends into the extracellular space for receptor binding [2]. FasLengages and trimerizes the death receptor Fas (CD95) on cellsurfaces to initiate the extrinsic apoptosis pathway [3]. The Fas-FasL interaction recruits the Fas-associated death domain adapterprotein (FADD) via death domain binding, which interacts withdimerized procaspase-8 to form the death-inducing signalingcomplex (DISC) [4]. Caspase-8 catalyzes its autoactivation,followed by the proteolytic conversion of downstream effectorcaspases such as caspase-3 and -7 into their mature forms [5].Effector caspases direct cell death by apoptosis, which results innuclear and cytoplasmic condensation followed by cellularfragmentation into membrane-bound apoptotic bodies [6].Caspase-activated DNase (CAD) cleaves genomic DNA betweennucleosomes to generate short fragments prior to cellularcondensation and membrane blebbing [7]. Membrane fragmentsare usually taken up by other cells and degraded in phagosomesvia a process known as efferocytosis. Efferocytosis of apoptotic cellscontributes to the resolution of inflammation by rapidly clearingcytotoxic cellular debris, and defects in this process can lead toinflammatory diseases such as acute lung injury [8].Although FasL is expressed by many cell types, it is primarilyrecognized as associated with activated T lymphocytes and naturalkiller (NK) cells. FasL-dependent apoptosis plays important rolesin tissue remodeling and the deletion of potentially autoreactivethymocytes to maintain immune tolerance during development,and it also contributes to tumor cell clearance by effector NK cells[9–11]. Though apoptosis has traditionally been defined asnoninflammatory during these processes, FasL-induced cell deathhas been shown to be highly proinflammatory in the context ofmicrobial infections [12].