Commuting (to) suicide: An update on nucleocytoplasmic transport in apoptosis
Patricia Grote, Karin Schaeuble, Elisa Ferrando-May"
Ulliversity of KOllstanz, Departmellt of Biology, Molecular Toxicology, P.O. Box X911, D 78457 KOllstallz, GermallY
Abstract
Commuting is the process of travelling between a place of residence and a place of work. In the context of biology, this expression evokes the continuous movement of macromolecules between different compartments of a eukaryotic cell. Transport in and out of the nucleus is a major example of intracellular commuting. This article discusses recent findings that substantiate the emerging link between nucleocytoplasmic transport and the signalling and execution of cell death.
KeYlVords: Caspase; Nuclear pore; DNA damage; Nuclear per~eability; Cellular stress; Ran; NFKB; GAPDH; PIDD; Virus
Interorganellar cross-talk has become a fundamental issue in the field of cell death by apoptosis. Distinct cel- lular organelles and compartments such as the mitochon- dria, the endoplasmic reticulum, the nucleus and the plasma membrane can be the source of primary signals that lead to cell killing [1,2]. Conversely, downstream effectors of cell death, primarily caspases, act at different subcellular sites to accomplish the dismantling of cellular structures. This dual role as initiator and victim of death signalling cascades is probably best exemplified by the cell nucleus, being on the one hand the origin of the cell's response to DNA damage, and on the other hand, a major substrate for the demolishing activity of the apoptotic execution machinery. Thus, the apparatus gov- erning the movement of molecules across the nuclear membrane has the potential to influence the cell death process on multiple levels. In fact, connections between nucleocytoplasmic transport and apoptosis have emerged in the past and have been summarized in two recent arti- cles [3,4]. In general, studies in the field have developed along three lines: (I) structural and functional alterations
• Corresponding author. Fax: +49 7531 884033.
Email address:Elisa.May@unikonstanz.de (E. Ferrando May).
of the nuclear pore complex (NPC) I in dying cells, (2) mechanisms of nuclear uptake/release of individual apo- ptosis mediators, and (3) stress-induced changes in global transport activity. The present mini review highlights some recent results related to each of these three topics.
For a more detailed introduction into the molecular biology of the NPC and the mechanisms of nuclear transport, several excellent review articles are available (e.g. [5 7]).
Stress- and pathogen-induced NPC dysfunction
A recent comprehensive analysis of the fate of the NPC in cell death by apoptosis [8] has confirmed and extended previous data on the caspase-mediated degradation of nuclear pore proteins [8 II]. According to these studies, both peripherally located nuclear pore proteins (Nups) as well as two Nups within the NPC core are degraded, while the overall structure of the pore remains intact. This is
I Abbreviations used: NPC, nuclear pore complex; PARP, poly (ADP) ribose polymerase; AIF, apoptosis inducing factor; GAPDH, glyceralde hyde 3 phosphate dehydrogenase; PIDD, p53 induced protein with a death domain; NO, nitric oxide; CA V, chicken anaemia virus.
First publ. in: Archives of Biochemistry and Biophysics ; 462 (2007), 2. - S. 156-161
Konstanzer Online-Publikations-System (KOPS) URL: http://nbn-resolving.de/urn:nbn:de:bsz:352-183222
thought to cause the collapse of the permeability barrier and to inhibit active transport, but conclusive data on the functional consequences of caspase-mediated NPC cleavage are still lacking. Other studies have proposed that NPC permeability may be altered in cells committed to die in the absence of any apparent disruption of nuclear pore· proteins [12,13] suggesting the existence of other mecha- nisms of NPC dysfunction.
Examples for such alternative, caspase-independent pathways for breaking the nucleocytoplasmic barrier come from virus-infected cells. The poliovirus 2A protease, for example, mediates, directly or indirectly, the cleavage of the nucleoporins Nupl53 and p62. Most remarkably and in contrast to what has been reported for apoptotic cells, virus infection is accompanied by structural disruption of the NPC as shown by electron microscopy [14 16]. In yeast, degradation of nucleoporins as a consequence of oxi- dative insult was shown to be mediated by Pep4p, a cathep- sin 0 homolog [17]. Here again, nuclear envelope permeability increased prior to the degradat'ion of nucleo- porins, supporting the notion that NPC function may be altered without damage to its components. In fact, these observations are consistent with the notion of the NPC as a dynamic, adaptive channel, whose conformation and functional properties are highly sensitive to changes in cel- lular activity [5]. Considering the diversity of pathways engaged by pathogens, by environmental noxa and by developmental cues, all potentially culminating in cell death, it is not surprising to observe variations in the mode of NE permeabilization depending on the death model sys- tem. Beside proteases, alterations of NPC structure and function during apoptosis could arise e.g. via calcium [18], or hydrophobic compounds such as proapoptotic lipid mediators [19,20] or the actin cytoskeleton [21,22]. The fact that multiple and possibly overlapping pathways may lead to the breakdown of the nucleocytoplasmic barrier in apoptosis marks a distinction between this process and . mitotic nuclear envelope disassembly, the latter ensuing from a specifically triggered, precisely orchestrated, and unique sequence of signalling events [23].
Apoptotic players moving in and out of the nucleus Poly-( ADP )-ribose (PAR)
PAR is one of the most interesting newcomers to the growing family of molecules that commute from and to the nucleus in cell death. Protein modification by poly- (ADP)-ribose results from the activity of the poly-(ADP)- ribose polymerase (PARP) family of enzymes. It has been initially described as an immediate response to DNA dam- age involved in the activation of several DNA repair path- ways. Additionally, and in particular in the nervous system, poly-(ADP)-ribosylation has been shown to medi- ate cell injury in response to ischemia and oxidative stress (for reviews see [24 26]). Pharmacological inhibitors of PARP-l, the founding member of the PARP family, as well
as disruption of the PARP-l gene, confer neuroprotection in cellular and animal models of ischemia and stroke [27,28]. Two papers have now pinpointed the molecular mechanism of PAR-mediated cytotoxicity: the PAR poly- mer itself acts as a death signal causing neuronal demise when its concentration is increased either by transfection or by downregulating the expression of PARG, the glyco- hydrolase responsible for PAR catabolism [29]. A key mediator of PAR-induced cell death is Apoptosis-Inducing Factor (AI F), a mitochondrial flavoprotein which was pre- viously shown to move to the nucleus during apoptosis and trigger chromatin condensation as well as high-molecular weight DNA fragmentation [30]. In the absence of PARP-l, the mitochondrial release of AIF is abrogated and cells are protected from death triggered by DNA dam- age, oxidative stress and excitotoxic insults [31]. Dawson and co-workers have now demonstrated that the PAR polymer acts as an AIF releasing factor [32]. In agreement with its role as nuclear-mitochondrial messenger, PAR appears in the cytosol and at the mitochondria of cortical neurons after NMDA receptor stimulation. An open and very relevant question arising in this context concerns the mechanism of PAR's nuclear extrusion. Only PAR poly- mers of at least 60 ADP-ribose units, corresponding to a minimum molecular weight of 33.6 kDa, display significant toxicity. Larger polymers can arise in vivo as a consequence of PARP-l activation [33,34]. In addition, it is not yet clear whether the deadly polymers exit the nucleus as free mole- cules or associated with a (protein) carrier. In any case, propagation of this signal is likely to be restricted by the size exclusion limit of the NPC which under normal condi- tions is in the range of about 40 kDa. Therefore, small vari- ations in NPC structure could have a huge impact on the efficiency of PAR signalling to the mitochondria. It is inter- esting in this respect that an increase in NPC permeability has been recently observed in cerebellar granule neurons undergoing cell death by excitotoxicity (Bano, D., and Nicotera P., pers. communication) .
p53-induced protein with a death domain (PIDD)
PlOD is a p53-inducible gene encoding a novel death domain-containing protein [35,36]. Initially characterized as a proapoptotic factor involved in the activation of cas- pase-2 after genotoxic damage [37,38], PlOD was subse- quently determined to participate in cell survival via the NFK-B pathway [39]. The molecular basis for these oppos- ing roles of PlOD lies in the interaction with different adaptors resulting in the formation of two distinct macro- molecular complexes, also termed PIDDosomes: RAIDD is essential for building the platform for activation of cas- pase-2, while RIPI bridges the interaction of PlOD with NEMO, a regulatory subunit of the IkB kinase complex.
The latter results in augmented SUMO-modification of NEMO and subsequent activation of NFK-B which then triggers the expression of antiapoptotic genes (for review see also [40]). The activity of PlOD as a molecular switch
between life and death is controlled by autoproteolysis and by the nucleocytoplasmic distribution of PIDD fragments, as described by a recent paper from J. Tschopp's group [41]. According to this model, PIDD is cleaved by autopro- teolysis in two fragments with distinct functions: PIDD-C, which is generated by an initial autoproteolytic step and PIDD-CC a shorter fragment, whose formation requires a second, delayed cleavage event. The kinetics of PIDD autoprocessing appear to depend strongly on the dose of the genotoxic insult: at high level of damage, the time delay between PIDD-C and PIDD-CC formation disappears and both fragments are induced simultaneously. Crucially, the only species showing interaction with RIP I, thus bearing the potential to initiate the modifications of NEMO that are required for NFK-B activation, is PIDD-C. In accor- dance with this, only PIDD-C is able to undergo nuclear translocation which is necessary for NEMO modification, following DNA damage. Only the shorter PIDD-CC frag- ment, on the other hand was found associated with RAIDD and was required for the activation of caspase-2.
An interesting open question in this context concerns the trigger for the nuclear uptake of PIDD-C, since this frag- ment is formed almost immediately after synthesis of the full-length protein but remains restricted to the cytoplasm unless the cells suffer DNA damage. The proposed unmasking of a nuclear localization site may thus require not only autoproteolysis but also a second damage-specific event. Altogether, the PIDD story provides a compelling example for the selective induction of signalling pathways by regulated subcellular localization.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
GAPDH is a well-known glycolytic enzyme which was shown to translocate to the nucleus in a number of model sys- tems of apoptosis [42]. Nuclear accumulation of GAPDH has been linked to cytotoxicity [43], but the molecular events underlying GAPDH-mediated cell death have been elusive.
Recently, S-nitrosylation of GAPDH by nitric oxide (NO) was reported to elicit a signalling pathway culminating in cell death [44]. Modification abolishes the catalytic activity and confers GAPDH with the ability to bind Siah, an E3 ubiqui- tin ligase. By virtue of Siah's nuclear localization signal, the complex translocates to the nucleus. Here, Siah is protected from its otherwise very rapid turnover through the interac- tion with GAPDH. Stabilized Siah induces the degradation of diverse target proteins and ultimately cell death.
Apoptin
Apoptin is a small protein from the chicken anaemia virus (CA V), which has attracted attention because it selectively induces apoptosis in tumor cells while leaving normal cells intact [45]. This tumor-specific killing activity has been related to cell-type dependent differences in its nucleocyto- plasmic distribution. In primary cells, Apoptin is localized to the cytoplasm, while in transformed cells it is found
primarily in the nucleus [46]. As demonstrated by recently published heterokaryon experiments [47], Apoptin is a bona fide nucleocytoplasmic shuttling protein possessing signals for nuclear import (NLS) and export (NES). Transformed cells display a cellular activity which negatively regulates the NES and favours the NLS, resulting in nuclear accumu- lation. Phosphorylation of a threonine residue adjacent to the N ES has been proposed as a candidate mechanism, since this is observed only in tumour cells and has been shown to inhibit nuclear export [46,48]. Intriguingly, the nuclear local- ization of Apoptin seems absolutely dependent on the spe- cific sequence of the Apoptin NES, which also harbours a multimerization domain: Apoptin mutants in which this sequence has been substituted for the NES of the HIV-Rev protein show the identical diffuse localization in both tumour and primary cells. On the other hand, several studies have demonstrated that nuclear localization per se is not sufficient for Apoptin-mediated cell death. A recent elegant study [47]
has put forward a model to reconcile, at least in part, some of the controversial observations concerning Apoptin's func- tion: according to this model, the critical factor in cell killing by Apoptin is not the steady state localization but rather its ability to shuttle between the nucleus and the cytoplasm.
Only Apoptin with functional transport signals (NES and NLS) is able to bind APCI, a mitotic regulator, and recruit it to PML bodies. In this way, Apoptin could mediate inhibi- tion of APCI resulting in G2/M arrest and subsequent apoptosis.
Inhibitors of apoptosis
Also, the activity of negative regulators of apoptosis is controlled by their nucleocytoplasmic localization. This has been investigated in detail in the case of XIAP and the clAPs (for a review, see [4]). In general, nuclear locali- zation of these inhibitors is regarded as a way to seclude them from their targets, active caspases present in the cyto- plasm. While this may bear significance forXIAP, the only member of the family being a bona fide caspase inhibitor [49], it is less likely to playa significant role in the antiap- optotic action of the clAPs, whose mechanism of action is less clear but may involve the ubiquitination and proteaso- mal degradation of caspases and other targets. In fact, enforced nuclear location of clAP I does not interfere with its ability to prevent apoptosis [50].
Recently, a nuclear export signal has been identified in one member of the BcI-2 family of apoptosis inhibitors, Bok [51]. Mutation of this NES results in nuclear accumu- lation and increases Bok's proapoptotic function. This is the first example of regulated nucleocytoplasmic shuttling of a bcl-2 family member.
Stress-induced alterations of nucleocytoplasmic transport:
cause or consequence of cell death?
Among the first alterations of the nucleocytoplasmic transport machinery observed under conditions of cellular
Table I
Nucleocytoplasmic transport of apoptosis related factors
Factor Translocation direction in Signals for active transport, regulation mechanisms Involvement of References
apoptosis caspases
AIF mito ---) nuc NLS, cytoplasmic retention (hsp70) Casp. indep. [30,60]
WOX I mito ---) nuc NLS n.d. [61]
Endo G mito ---) nuc No obvious transport signals n.d. [62]
ARTS mito ---) nuc n.d. Casp. dep. [63,64]
PAK5 mito ---) nllc NLS, NES n.d. [65]
DEDD cyto ---) nliC NLS, NES, lIbiqllitination cytoplasmic retention Casp. dep. [55,66]
(cytokeratins)
TRADD cyto ---) nuc NLS, NES cytoplasmic retention (cytokeratins) n.d. [67,68]
Apaf I cyto ---) nuc Mediated by nucling n.d. [69]
010 I cyto ---) nliC NLS, phosphorylation n.d. [70]
GAPDH cyto ---) nllc Mediated by siah I n.d. [44]
MSTI cyto ---) nllc NLS, NES, phosphorylation Casp. dep. [71,72]
PAK2 cyto ---) nuc NLS, NES Casp. dep. [73]
Helicard cyto ---) nuc n.d. Casp. dep. [74]
CAD/DFF40 cyto ---) nuc NLS Casp. dep. [75.76]
HDAC4 cyto ---) nuc NLS, NES Casp. dep. [77,78]
Apoptin cyto ---) nliC NES, NLS n.d. [46 48]
PTEN cyto ---) nllc NLS n.d. [58,79]
Caspase 3 cyto ---) nliC Mediated by AKAP95 n.d. [80]
DAXX nuc ---) cyto NLS, NES, phosphorylation n.d. [81,82]
Nur77/TR3 nuc ---) mito NLS, NES, phosphorylation n.d. [83 85]
p53 nllc---) mito NLS, NES, lIbiqllitination n.d. [86]
Histone H 1.2 nllc---) mito Active import by importin p/importin 7 Casp. indep. [87]
Caspase 2 nllc---) mito NLS Casp. dep. [88,89]
PAR nuc ---) mito n.d. Casp. indep. [29,32]
FADD cyto +-> nllc NLS, NES (exportin 5), phosphorylation n.d. [90,91]
PEA 15 cyto +-> nllc NES
stress is an increase of the cytoplasmic concentration of Ran, a small GTPase controlling the direction of nuclear transport. In unperturbed cells, Ran localizes predomi- nantly to the nucleus as Ran-GTP, whereas it is found in the cytoplasm after treatment with different apoptosis- inducing agents (for a summary see [3]). Ran exiting the nucleus is converted to the GDP-bound form by its GTPase activating protein, RanGAP, located at the cyto- plasmic side of the NPC. Thus, leakage of Ran out of the nucleus is expected to deplete the cellular pool of Ran- GTP. Reduced levels of Ran-GTP, in turn, are responsible for the inhibition of nuclear import that is observed in A TP depleted cells [52]. In line with these results, Yasuda et ai., have reported that the appearance of cytoplasmic Ran fol- lowing oxidative stress, heat shock and UV irradiation is the consequence of a decreased intracellular A TP pool [53). Import inhibition in cells with low Ran-GTP corre- lates with nuclear accumulation of the classical import fac- tor importin-ex [13,52,53). The physiological outcome of importin-ex nuclear sequestration may vary depending on which of the six known isoforms of this protein is affected [54) and which substrates thus fail to be transported. For example, reduced nuclear uptake of proapoptotic factors with a classical NLS, such as AIF [30) or DEDD [55) should have a protective effect. Consistent with this assumption is the observation that partial inhibition of nuclear import by WGA, GTP-yS or excess amounts of NTF2 or importin-ex may delay cell demise [56). In this
n.d. [92,93]
respect, extrusion of Ran out of the nucleus may be regarded as a strategy to promote survival by counteract- ing the relay of death signals to the nucleus. There is no evi- dence yet to support this mechanism. Nevertheless, one can predict that it will most likely play a role in cells which loose the ability to produce sufficient ATP at an early stage after injury and will thus not die by typical apoptosis. In fact, preservation of ATP levels is a distinguishing feature of apoptotic cell death [57), and nuclear import was shown to be functional in different model systems of apoptosis [58, and own unpublished observations).
On the other hand, a protracted and substantial inhibi- tion of nuclear transport can per se trigger cell death, as shown for CC3, a proapoptotic protein capable of forming stable complexes with import receptors and blocking multi- ple nuclear import pathways. Whether alterations of the nuclear transport system may be cause or consequence, antagonize or exacerbate cell death, is thus an intricate question. While we are appreciating that nuclear transport is an integral part of death signalling, it also becomes clear that death pathways may be regplated by nuclear transport at different levels and with different outcomes depending on the cellular context and the type of insult.
Conclusion
There is plenty of evidence in the literature that both the nuclear uptake and release of apoptotic factors play
important roles in the initiation and execution of the apop- totic program. The interest in elucidating the mechanisms involved in regulating the subcellular localization of such factors is thus steadily increasing. During the past year, several newcomers have joined the list of apoptotic players whose function is controlled by nucleocytoplasmic trans- port (see Table I). More remarkably, novel mechanisms for the relay of apoptotic signals from and to the nucleus have emerged. This is the case for PAR, which represents a novel type of nucleo-mitochondrial messenger molecule, and for GAPDH, the erstwhile enigmatic promoter of cell death in the nucleus, now identified as an interactor of the E3 ubiquitin ligase Siahl. On the other hand, as the bio- physical principles that govern the passage through the nuclear pore become accessible [59] significant progress is to be expected in our understanding of how changes in cel- lular activity may translate into alterations of nuclear transport.
Acknowledgments
We wish to thank Evelyn O'Brien for critical reading of the manuscript and J6rg Fahrer for helpful informations on PAR metabolism.
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