The Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK.
FEBS J. 2020 Oct;287(19):4246-4260. doi: 10.1111/febs.15260. Epub 2020 Mar 12.
Possessing structural homology with their active enzyme counterparts but lacking catalytic activity, pseudoenzymes have been identified for all major enzyme groups. Caspases are a family of cysteine-dependent aspartate-directed proteases that play essential roles in regulating cell death and inflammation. Here, we discuss the only human pseudo-caspase, FLIP(L), a paralog of the apoptosis-initiating caspases, caspase-8 and caspase-10. FLIP(L) has been shown to play a key role in regulating the processing and activity of caspase-8, thereby modulating apoptotic signaling mediated by death receptors (such as TRAIL-R1/R2), TNF receptor-1 (TNFR1), and Toll-like receptors. In this review, these canonical roles of FLIP(L) are discussed. Additionally, a range of nonclassical pseudoenzyme roles are described, in which FLIP(L) functions independently of caspase-8. These nonclassical pseudoenzyme functions enable FLIP(L) to play key roles in the regulation of a wide range of biological processes beyond its canonical roles as a modulator of cell death.
具有与其活性酶对应物结构同源性但缺乏催化活性的伪酶已被鉴定为所有主要的酶类。天冬氨酸特异性半胱氨酸蛋白酶（caspases）是一类在调节细胞死亡和炎症中发挥重要作用的半胱氨酸依赖性天冬氨酸蛋白酶。在这里，我们讨论了唯一的人类伪半胱天冬酶，FLIP（L），它是起始凋亡的半胱天冬酶 caspase-8 和 caspase-10 的旁系同源物。FLIP（L）已被证明在调节 caspase-8 的加工和活性方面发挥关键作用，从而调节死亡受体（如 TRAIL-R1/R2、TNF 受体-1（TNFR1）和 Toll 样受体）介导的凋亡信号。在这篇综述中，讨论了 FLIP（L）的这些典型作用。此外，还描述了一系列非经典的伪酶作用，其中 FLIP（L）独立于 caspase-8 发挥作用。这些非经典的伪酶作用使 FLIP（L）能够在其作为细胞死亡调节剂的典型作用之外，在广泛的生物学过程的调节中发挥关键作用。
