FLIP(L): the pseudo-caspase.

Peter Smyth,Tamas Sessler,Christopher J Scott,Daniel B Longley

doi:10.1111/febs.15260

Abstract

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.

Highlights

Identified over 50 years ago, pseudoenzymes have recently been the subject of increased interest as the originally unanticipated extent of their biological importance has become apparent [1]
Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) in response to damage-associated molecular patterns (DAMPs)/pathogen-associated molecular pattern (PAMP)-mediated activation of toll-like receptors (TLRs) upregulates expression of the IL precursor cytokines and NLRP3 itself [63]. This is followed by the formation of the inflammasome complex, comprising NLRP3, procaspase-1, and the adaptor protein apoptosis-associated speck-like protein containing CARD (ASC), at which procaspase-1 oligomerization results in its activation with subsequent cleavage and activation of pro-IL-1b and pro-IL-18 [64]
Procaspase-8 has been shown to modulate the inflammasome, these functions, which are specific for the long FLIP splice form, are not reported to be caspase-8-dependent and are examples of FLIP(L) acting in a nonclassic pseudoenzyme manner [67]

Summary

Introduction

Identified over 50 years ago, pseudoenzymes have recently been the subject of increased interest as the originally unanticipated extent of their biological importance has become apparent [1]. At low levels of receptor activation, the number of DISCs formed will be low and there will be a predominance of heterodimers (FLIP(L):procaspase-8 ratio ~ 1 : 1) and apoptosis will be inhibited (scenario 1).

Results

Conclusion