Schneider P, Holler N, Bodmer J L, Hahne M, Frei K, Fontana A, Tschopp J
Institute of Biochemistry, University of Lausanne, BIL Research Centre, CH-1066 Epalinges, Switzerland.
J Exp Med. 1998 Apr 20;187(8):1205-13. doi: 10.1084/jem.187.8.1205.
Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)-alpha undergo metalloproteinase-mediated proteolytic processing in their extracellular domains resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF-alpha) which, in the case of sFasL, is thought to be implicated in diseases such as hepatitis and AIDS. Here we show that the processing of sFasL occurs between Ser126 and Leu127. The apoptotic-inducing capacity of naturally processed sFasL was reduced by >1,000-fold compared with membrane-bound FasL, and injection of high doses of recombinant sFasL in mice did not induce liver failure. However, soluble FasL retained its capacity to interact with Fas, and restoration of its cytotoxic activity was achieved both in vitro and in vivo with the addition of cross-linking antibodies. Similarly, the marginal apoptotic activity of recombinant soluble TNF-related apoptosis-inducing ligand (sTRAIL), another member of the TNF ligand family, was greatly increased upon cross-linking. These results indicate that the mere trimerization of the Fas and TRAIL receptors may not be sufficient to trigger death signals. Thus, the observation that sFasL is less cytotoxic than membrane-bound FasL may explain why in certain types of cancer, systemic tissue damage is not detected, even though the levels of circulating sFasL are high.
人类Fas配体（L）（CD95L）和肿瘤坏死因子（TNF）-α在其细胞外结构域经历金属蛋白酶介导的蛋白水解过程，导致可溶性三聚体配体（可溶性[s]FasL、sTNF-α）的释放，就sFasL而言，人们认为它与肝炎和艾滋病等疾病有关。在此我们表明，sFasL的加工过程发生在Ser126和Leu127之间。与膜结合的FasL相比，天然加工的sFasL的凋亡诱导能力降低了1000倍以上，并且在小鼠中注射高剂量的重组sFasL不会诱导肝衰竭。然而，可溶性FasL保留了其与Fas相互作用的能力，并且通过添加交联抗体在体外和体内都恢复了其细胞毒性活性。同样，TNF配体家族的另一个成员重组可溶性TNF相关凋亡诱导配体（sTRAIL）的微弱凋亡活性在交联后大大增加。这些结果表明，仅仅Fas和TRAIL受体的三聚化可能不足以触发死亡信号。因此，sFasL的细胞毒性低于膜结合的FasL这一观察结果可以解释为什么在某些类型的癌症中，即使循环中的sFasL水平很高，也检测不到全身性组织损伤。
