Caspase-2: the orphan caspase

Abstract

Despite an abundance of literature on the role of caspase-2 in apoptosis, there exists much controversy about this protease making it difficult to place caspase-2 correctly in the apoptotic cascade, and hence its role in apoptosis remains unclear. The identification of the PIDDosome as a signaling platform for caspase-2 activation prompted intense investigation into the true role of this orphan caspase. What has emerged is the idea that caspase-2 may not be mandatory for apoptosis and that activation of this caspase in response to some forms of stress has other effects on the cell such as regulation of cell cycle progression. This idea is particularly relevent to the discovery that caspase-2 may act as a tumor suppressor. Here, we discuss the proposed mechanisms through which caspase-2 signals, in particular those involving PIDD, and their impact on cellular fate.

Figure 1

Domain organization of the PIDDosome components. The PIDDosome is comprised of the proteins PIDD, RAIDD and caspase-2. The cleavage fragments resulting from PIDD autoprocessing are indicated

Figure 2

A model of the PIDDosome for caspase-2 activation. The schematic model is based on the crystal structure of the PIDD-DD:RAIDD-DD core complex, which forms the center rings mediating oligomerization. The RAIDD CARD occupies the outer part of the PIDDosome bringing seven caspase-2 molecules into proximity facilitating dimerization. Adapted from Park et al

Figure 3

Model of PIDD maturation and complex assembly. PIDD is cleaved at S446 to generate PIDD-N and PIDD-C. PIDD-C translocates to the nucleus where it recruites RIPK1 and NEMO, which triggers NFκB activation. Additional processing of PIDD at S588 produces PIDD-CC, which binds to RAIDD in the cytoplasm, which recruits and activates caspase-2. Adapted from Tinel et al

Figure 4

Caspase-2 pathways to apoptosis and cell cycle arrest. In response to cellular stresses PIDD activates caspase-2. Active caspase-2 cleaves Bid to form tBid, which induces mitochondrial outer membrane permeabilization. Active caspase-2 also cleaves MDM2 to form MDM2 p60, which binds to and stabilizes p53. p53 induces PIDD expression resulting in a feed-forward loop. Caspase-2 is also activated by ATM/ATR independently of p53 when Chk1 activity is repressed