Non-apoptotic Functions Of Caspases Research Articles

Various functions of caspases in hematopoiesis

The role of cysteine proteases of the caspase family in apoptosis is well defined. Some caspases were initially shown to be involved in cytokine maturation along inflammatory response. In the recent years, several other non apoptotic functions of caspases were identified. In hematopoietic cells, caspases play a role in specific pathways of differentiation (erythropoiesis, differentiation of monocytes into macrophages, formation of proplatelets by megakaryocytes). These enzymes also play a non-apoptotic and complex role in regulating the maturation and proliferation of specific lymphocytes. Lastly, the apoptotic functions of caspases regulate the life span of several but not all blood cell types. The present review summarizes the current knowledge in these different functions. We show that the nature of involved enzymes, the pathways leading to their activation and the specificity of their cellular target proteins varies strongly from a cell type to another. We indicate also that, in most situations, specific Bcl-2-related proteins are involved in the control of caspase activation. Lastly, we discuss the deregulation of these pathways in hematopoietic diseases, including those in which an excess in caspase activation leads to cell death and those in which a default in caspase activation could block cell differentiation.

Distinct Mechanisms of Apoptosis-Induced Compensatory Proliferation in Proliferating and Differentiating Tissues in the Drosophila Eye

In multicellular organisms, apoptotic cells induce compensatory proliferation of neighboring cells to maintain tissue homeostasis. In the Drosophila wing imaginal disc, dying cells trigger compensatory proliferation through secretion of the mitogens Decapentaplegic (Dpp) and Wingless (Wg). This process is under control of the initiator caspase Dronc, but not effector caspases. Here we show that a second mechanism of apoptosis-induced compensatory proliferation exists. This mechanism is dependent on effector caspases which trigger the activation of Hedgehog (Hh) signaling for compensatory proliferation. Furthermore, whereas Dpp and Wg signaling is preferentially employed in apoptotic proliferating tissues, Hh signaling is activated in differentiating eye tissues. Interestingly, effector caspases in photoreceptor neurons stimulate Hh signaling which triggers cell-cycle reentry of cells that had previously exited the cell cycle. In summary, dependent on the developmental potential of the affected tissue, different caspases trigger distinct forms of compensatory proliferation in an apparent nonapoptotic function.

Possible involvement of DNA breaks in epigenetic regulation of cell differentiation

The review summarizes the authors' and literature data on accumulation of DNA breaks in differentiating cells. Large 50-kb free DNA fragments were observed by several research teams in non-apoptotic insect, mammal, and plant cells. More intense DNA breakage was observed during maturation of spermatides, embryo development, and differentiation of myotubes, epidermal cells, lymphocytes, and neutrophils. In general, accumulation of DNA breaks in differentiating cells cannot be attributed to a decrease in the DNA repair efficiency. Poly(ADP)ribose synthesis often follows the DNA breakage in differentiating cells. We hypothesize that DNA fragmentation is an epigenetic tool for regulating the differentiation process. Scarce data on localization of the differentiation-associated DNA breaks indicate their preferable accumulation in specific DNA sequences including the nuclear matrix attachment sites. he same sites are degraded at early stages of apoptosis. Recent data on non-apoptotic function of caspases provide more evidence for possible existence of a DNA breakage mechanism in differentiating cells, resembling the initial stage of apoptosis. Excision of methylated cytosine and recombination are other possible explanations of the phenomenon. Elucidation of mechanisms of differentiation-induced DNA breaks appears to be a prospective research direction.

Possible involvement of DNA strand breaks in regulation of cell differentiation.

The present review summarizes data on the accumulation of DNA strand breaks in differentiating cells. Large 50 Kbp free DNA fragments were observed by several research teams in non-apoptotic insect, mammal and plant cells. A more intensive DNA breakage was observed during maturation of spermatides, embryo development, and differentiation of myotubes, epidermal cells, lymphocytes and neutrophils. In general, accumulation of DNA strand breaks in differentiating cells cannot be attributed to decrease of the DNA repair efficiency. Poly(ADP)ribose synthesis often follows the DNA breakage in differentiating cells. We hypothesize that DNA fragmentation is an epigenetic tool for regulation of the differentiation process. Scarce data on localization of the differentiation-associated DNA strand breaks indicate their preferred accumulation in specific DNA sequences including the nuclear matrix attachment sites and repeats. Recent data on non-apoptotic functions of caspases provide more evidence for possible existence of a DNA breakage mechanism in differentiating cells resembling the initial stage of apoptosis. Excision of methylated cytosine and recombination are other possible explanations of the phenomenon. Elucidation of mechanisms of differentiation-induced DNA strand breaks appears to possess considerable research potential.

Caspases in cell survival, proliferation and differentiation

Caspases, a family of evolutionarily, conserved cysteinyl proteases, mediate both apoptosis and inflammation through aspartate-specific cleavage of a wide number of cellular substrates. Most substrates of apoptotic caspases have been conotated with cellular dismantling, while inflammatory caspases mediate the proteolytic activation of inflammatory cytokines. Through detailed functional analysis of conditional caspase-deficient mice or derived cells, caspase biology has been extended to cellular responses such as cell differentiation, proliferation and NF-kappaB activation. Here, we discuss recent data indicating that non-apoptotic functions of caspases involve proteolysis exerted by their catalytic domains as well as non-proteolytic functions exerted by their prodomains. Homotypic oligomerization motifs in the latter mediate the recruitment of adaptors and effectors that modulate NF-kappaB activation. The non-apoptotic functions of caspases suggest that they may become activated independently of--or without--inducing an apoptotic cascade. Moreover, the existence of non-catalytic caspase-like molecules such as human caspase-12, c-FLIP and CARD-only proteins further supports the non-proteolytic functions of caspases in the regulation of cell survival, proliferation, differentiation and inflammation.

IKK and Caspases in Regulating Cell Shape

Two reports this week provide evidence that in Drosophila IKKε, a kinase of the IKK family, which stands for inhibitor of nuclear factor κB (NF-κB) kinase, promotes the degradation of DIAP1, the Drosophila inhibitor of apoptosis protein, and activates the DRONC caspase to regulate nonapoptotic processes. Kuranaga et al. found mutant forms of IKKε lacking kinase activity in a screen for suppressors of cell death. Although overexpression of IKKε did promote cell death, knockdown of IKKε did not suppress cell death, suggesting that the IKKε may have a nonapoptotic function. IKKε promoted the phosphorylation of DIAP1 and the degradation of DIAP1 in S2 cells. Although the two proteins coimmunoprecipitated from S2 cells, purified proteins did not physically interact, suggesting that the interaction may be indirect. In wing discs, mild caspase activation was detected in the absence of apoptosis, and this caspase activation was inhibited when IKKε was knocked down. Oshima et al. showed that overexpression of IKKε disrupted epithelial integrity in the Drosophila embryo tracheal system, and this was associated with a loss of apical F actin and loss of cell polarity in the epithelial cells. In S2 cells, altering the abundance of IKKε altered cell morphology, with decreased IKKε stimulating the frequency of serrate- or stellate-shaped cells and decreasing retrograde F actin flow and increased IKKε stimulating membrane ruffling and increasing retrograde F actin flow. In the trachea, sensory bristles, and antenna arista, inhibition of IKKε promoted excessive branching of the structures, which was consistent with disruption in actin regulation. Genetic interactions were observed in the arista phenotype between IKKε, DIAP1, and DRONC, suggesting that IKKε regulates the F actin cytoskeleton by stimulating caspase activity. Thus, these two results uncover a novel activation of caspases through an IKK and a nonapoptotic function for caspases in regulating the actin cytoskeleton. (Bergmann and Montell discuss the implications of these findings.) E. Kuranaga, H. Kanuka, A. Tonoki, K. Takemoto, T. Tomioka, M. Kobayashi, S. Hayashi, M. Miura, Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. Cell 126 , 583-596 (2006). [PubMed] K. Oshima, M. Takeda, E. Kuranaga, R. Ueda, T. Aigaki, M. Miura, S. Hayashi, IKKε regulates F actin assembly and interacts with Drosophila IAP1 in cellular morphogenesis. Curr. Biol. 16 , 1531-1537 (2006). [PubMed] A. Bergmann, IKKε signaling: Not just NF-κB. Curr. Biol. 16 , R588-R590 (2006). [PubMed] D. J. Montell, A kinase gets caspases into shape. Cell 126 , 450-452 (2006). [PubMed]

Caspase Function and the Immune System

Caspases are key effector components of apoptosis, the process of programmed cell death. However, a large body of recent work has shown that caspase activity is necessary for several nonapoptotic cellular functions, such as proliferation, differentiation, survival, and the regulation of cytokine expression. In this review, we concentrate on the nonapoptotic functions of caspases and, in particular, on nonapoptotic roles of caspases in the immune system. Because of the involvement of caspases in promoting cell death, as well as cell proliferation and other nonapoptotic functions, studies involving the inhibition of caspases in vivo must be interpreted with caution.

Vital functions for lethal caspases

Caspases are a family of cysteine proteases expressed as inactive zymogens in virtually all animal cells. These enzymes play a central role in most cell death pathways leading to apoptosis but growing evidences implicate caspases also in nonapoptotic functions. Several of these enzymes, activated in molecular platforms referred to as inflammasomes, play a role in innate immune response by processing some of the cytokines involved in inflammatory response. Caspases are requested for terminal differentiation of specific cell types, whether this differentiation process leads to enucleation or not. These enzymes play also a role in T and B lymphocyte proliferation and, in some circumstances, appear to be cytoprotective rather than cytotoxic. These pleiotropic functions implicate caspases in the control of life and death but the fine regulation of their dual effect remains poorly understood. The nonapoptotic functions of caspases implicate that cells can restrict the proteolytic activity of these enzymes to selected substrates. Deregulation of the pathways in which caspases exert these nonapoptotic functions is suspected to play a role in the pathophysiology of several human diseases.

Non-apoptotic functions of caspases in cellular proliferation and differentiation

The cysteinyl aspartate-specific proteases (caspases) have been identified as key players in the cellular process termed programmed cell death or apoptosis. During apoptosis, activated apoptotic caspases cleave selected target proteins to execute cell death. Additionally to their established function in cell death, a variety of recent publications have provided increasing evidence that apoptotic caspases also participate in several non-apoptotic cellular processes. Activated caspases exhibit functions during T-cell proliferation and cell cycle regulation, but are also involved in the differentiation of a diverse array of cell types. In some cell types, their differentiation can be morphologically viewed as a kind of incomplete apoptosis. Analysis of well-known apoptotic targets of caspases implicates that the cleavage of a limited number of selected substrates plays a major role during non-apoptotic functions of caspases. Selective substrate cleavage might be regulated by activation of anti-apoptotic factors, via a compartmentalized activation of caspases, or through limited activity of caspases during apoptosis-independent functions. The increasing evidence for caspase function in non-apoptotic cellular events suggests that caspases play a much more diverse role than previously assumed.