Noncaspase proteases in apoptosis

Abstract

Biochemical and genetic analysis of apoptosis has determined that intracellular proteases are key effectors of cell death pathways. In particular, early studies have pointed to the primacy of caspase proteases as mediators of execution. More recently, however, evidence has accumulated that noncaspases, including cathepsins, calpains, granzymes, and the proteasome complex, also have roles in mediating and promoting cell death. An important goal is to understand the importance of distinct noncaspases in various forms of apoptosis, and to determine whether pathways mediated by noncaspase proteases intersect with those mediated by caspases. In this review the roles of noncaspase proteases in the biochemistry of apoptosis will be discussed. Leukemia (2000) 14, 1695-1703.

Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release

“…Indeed, all reagents precluding the AIF mitochondrial processing (including proteasome inhibitors) inhibit two major families of cystein proteases: calpains and cathepsins. [16][17][18] However, as calpains are inactive enzymes in the Atr calcium-depleted system (Figure 1c), our results point toward a cathepsin implication in Ca 2 þ -independent AIF processing. Thus, we looked for an individual cathepsin protease integrating the results presented above.…”

“…B, L, and S). 18 Intriguingly, only the cathepsin cystein proteases B, L, and S cleaved mouse recombinant AIF (Figure 1i and data …”

“…In a cellular context, and when caspases are placed upstream of lysosomes and mitochondria, our work supports the previously reported possibility that caspases increase lysosomal or mitochondrial permeabilization, thereby provoking cathepsin and/or calpain activation. 18,20 This activation might cause further AIF cleavage and release. In this case, the sequence of cell death events describes a single-cell death pathway that includes both caspases and other caspase-independent effectors like cathepsins, calpains, or AIF.…”

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

“…Both pathways converge and activate executioner caspase-3, which then cleaves intracellular protein substrates and causes cell death. There is now accumulating evidence indicating that PCD can also occur in complete absence and independently of caspase activation (Johnson, 2000;Jaattela and Tschopp, 2003;Lockshin and Zakeri, 2004;Broker et al, 2005). Several models of caspase-independent PCD have been described.…”

“…Caspase-independent cell death pathways are important mechanisms for triggering a response to cytotoxic agents or other death stimuli when the caspase-mediated routes fail. These pathways may involve organelles such as lysosomes and the endoplasmic reticulum via the activation of non-caspases proteases such as cathepsins or calpains (Johnson, 2000). However, the mitochondrion plays a central role in caspase-independent cell death as in caspase-dependent apoptosis .…”