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Viral Hijacking of Host Caspases: an Emerging Category of Pathogen&Ndash Cell Death and Differentiation (2017) 24, 1401–1410 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17 www.nature.com/cdd Review Viral hijacking of host caspases: an emerging category of pathogen–host interactions Patrick F Connolly1 and Howard O Fearnhead*,1 Viruses co-evolve with their hosts, and many viruses have developed mechanisms to suppress or modify the host cell apoptotic response for their own benefit. Recently, evidence has emerged for the opposite strategy. Some viruses have developed the ability to co-opt apoptotic caspase activity to facilitate their own proliferation. In these strategies, viral proteins are cleaved by host caspases to create cleavage products with novel activities which facilitate viral replication. This represents a novel and interesting class of viral–host interactions, and also represents a new group of non-apoptotic roles for caspases. Here we review the evidence for such strategies, and discuss their origins and their implications for our understanding of the relationship between viral pathogenesis and programmed cell death. Cell Death and Differentiation (2017) 24, 1401–1410; doi:10.1038/cdd.2017.59; published online 19 May 2017 Bullet Points It is also important to note that even during apoptosis, caspases engage not only in destructive cleavage, but also Facts engage in productive cleavage: cleavage which produces de novo activities of the substrate protein. This is achieved Executioner caspases have many non-apoptotic roles. through several mechanisms (Figure 1), such as removal of Many viruses modulate the host cell apoptotic response. autoinhibitory domains to produce constitutively active Some viruses utilize caspases to perform proteolytic enzymes, cleavage of cytoplasmic localization sequences to processing of viral components. facilitate nuclear membrane transition, or degradation of Caspase-3 and -7 predominate, although caspase-6 upstream inhibitory factors in metabolic pathways to activate – cleavage is also used. downstream factors.3 6 Such productive cleavage allows Open questions apoptotic cells to engage signaling pathways until late in the cell death process. How widespread is this phenomenon? No systematic Host cell apoptosis is a common response to viral infection et al 7 experiments have yet been published. (reviewed in Galluzzi . ). Apoptosis is typically considered Can these examples be classified into functional a defense mechanism which kills the infected cell in order to categories? protect the organism as a whole. As a result of this, there is a Did this ‘hijacking’ emerge once or several times during selection pressure in favor of viruses which have evolved evolution? mechanisms to block apoptosis. For example, several viruses Are other modalities of cell death manipulated in this way? encode Bcl-2 homologs or homologs of cFLIP which function to inhibit activation of apoptotic caspases and block death of 8–16 Caspases can be classed into three broad categories (Table 1): the host cell. those which function as the proteolytic executioners of Interestingly, the inverse strategy can also be observed. apoptosis (‘killer’ caspases; including -3 and -7), those which Some viruses actually exploit host cell caspase activity serve to activate the executioner caspases (initiator caspases; to facilitate their own replication. These viruses encode including -8 and -10), and those which have roles in non- gene products with canonical caspase cleavage motifs, apoptotic processes, including inflammatory caspases such and cleavage at these sites produces products with as -1, -5 and -11 (reviewed in Earnshaw et al.1 and Martinon additional functions. This caspase cleavage is used, for and Tschopp2). example, to facilitate nuclear translocation of viral compo- In recent years it has become clear that ‘killer’ caspases nents, to activate viral-encoded host transcriptional modifiers, have roles in diverse non-apoptotic processes, such as cell or to perform final maturation of virion particles (summarized in differentiation, migration and metastasis, and in signaling Table 2). (reviewed in other articles in this issue). In these non-apoptotic The involvement of host caspases in both viral and bacterial processes, the extent of caspase activation or its subcellular pathogenesis has previously been reviewed.17,18 However the localization is restricted in order to prevent cell death. present review focuses solely on examples of host caspase 1Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, Galway, Ireland *Corresponding author: H Fearnhead, Pharmacology and Therapeutics National University of Ireland, Galway, Biomedical Sciences Building Newcastle Road Room BMS-G029 NUI Galway, Dangan, Galway H91 CF50, Ireland; Tel: +353 91 495240. E-mail: [email protected] Received 17.1.17; revised 14.3.17; accepted 27.3.17; Edited by E Arama; published online 19.5.17 1402 Cell Death and Differentiation CDK1) through inactivation of upstreaminhibitor inhibitory partners factors (ICAD/CAD), in through biochemical removalsignaling of pathways factors autoinhibitory or (Wee1/ domains enzymes (PAK2), are or activated. Thisexecutioner can be caspases through degradation can of bound disassembling also the engage cytoskeleton through induring cleavage apoptosis. of productive Executioner actin caspases cleavage can filaments engage (right), (left). in destructive However, cleavage, in such as which As such, a review of thecaspase current state interactions of this being research published ishas timely. at an continued increasedapoptosis to pace. as develop, progeny withcleavage dissemination of viral mechanism. proteins new rather This than, examples for example, field induction of of virus Figure 1 functions. differentiation (cornification). Capsasesthe conventional 16 groups. Caspase-14apoptosis appears initiators to and function apoptosis onlyCaspases executioners. are in Some typically keratinocyte caspases grouped into lie three outside major of types: inflammatory caspases, Unknown functionsKeratinocyte differentiationApoptotic executioner Caspase-14 Caspase-16Apoptotic initiator Caspase-3 119 120 Inflammatory responseFunctional group 116 Caspase-2Table 1 Caspase-1 111 Name 105 Ref Conventional roles of caspases in cell death and inflammation 119 Examples of destructive and productive cleavage events by caspases – 18 have not yet been ascribed Caspase-18Caspase-17Caspase-7Caspase-6 120 120 Caspase-15Caspase-10Caspase-9 118 Caspase-8 117 Caspase-13 115 Caspase-12 114 Caspase-11 113 Caspase-5 112 Caspase-4 110 109 108 107 106 Viral hijacking of host caspases PF Connolly and HO Fearnhead – Table 2 Summary of examples of productive caspase cleavage presented in this review Family Species Protein Protein role Caspase Cleavage site Consequence of cleavage Primary (full length) reference Parvoviridae Amdovirus NS1 Gene transcription and 3 INTD/227, DQTD/285 Cleaved NS1 acts as a chaperone to deliver full- 26 translation (590) length NS1 to nucleus Orthomyxoviridae Influenza A NP Structural protein 3 METD/16 (498) Removal of nuclear localization sequence, 30 translocation of ribonucleoprotein complexes to cytoplasm Flaviviridae Hepacivirus C NS5A Modulates host gene tran- 3 TELD/154, SAVD/389 Exposure of nuclear localization sequence, 46 scription and inflammatory (447) removal of cytoplasmic localization sequence. response Translocation of NS5A to nucleus Flaviviridae Classical swine fever NS5A Viral genome translation 6 DTTD/275 (497) Unknown. Viral replication severely impaired 84 virus under caspase-6 inhibition Papillomaviridae Human E1 DNA helicase 3/7 DMVD/49 (629) Facilitates viral genome amplification. May 58 papillomavirus expose a KRK nuclear localization signal. Adenoviridae Adenovirus-12 E1A-12S/ Modulates host gene 3 HLVD/24, FQLD/150, Disrupts binding to CBP and TBP and enhances 66 13S transcription STLD/204, SILD/222 binding to CTBP1 (266) Astroviridae Mamastrovirus VP90 Structural protein 3 TYVD/657 (782) VP90 processed into mature VP70. Contributes 75 to viral release Reoviridae Avian reovirus μNS Assembly of viral factories 3 DSPD/154 (635) Probably facilitates factory dissolution upon 80 completion of viral assembly For each viral protein, the responsible caspase, cleavage site, consequence of cleavage, and primary reference are summarized. Viral hijacking of host caspases PF Connolly and HO Fearnhead 1403 Cleavage to Induce Nuclear-Cytoplasmic Trafficking of Influenza A. Influenza viruses are members of the Ortho- Viral Components myxoviridae, a large family of ( − )ssRNA enveloped viruses which infect birds and mammals. There are currently three Amdovirus. The Aleutian mink disease parvovirus (AMDV, recognized subtypes of influenza, termed A, B and C.27 All Amdovirus) is a small, nonenveloped, (− )ssDNA virus.19 It Influenza subtypes share similar overall structure, consisting harbors a 4.7 kbp genome encoding two open reading of a lipid outer envelope, a capsid shell and a genomic frames, early ORF1 and late ORF2.20 ribonucleoprotein complex.28 ADV infects both newborn and adult minks, but with rather Caspase activity is required for replication of several different cytopathologies. In newborn minks, infection leads to pathogenic H7N7, H3N2 and H1N1 strains.29–31 Inhibition of rampant, permissive replication, causing apoptosis of the host caspase activity using z-DEVD.FMK causes significant cell. In adult minks, ADV maintains itself through a more replication deficiencies in
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