Caspase-2: an orphan enzyme out of the shadows

Forsberg, Jeremy; Zhivotovsky, Boris; Olsson, Magnus

doi:10.1038/onc.2017.169

Cited by 16 publications

(10 citation statements)

References 51 publications

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“…There are nine genes annotated as being involved in apoptosis, a process that can be initiated if a cell fails a mitotic check point. CASP2, long considered to be an orphan caspase 72 , is recognised as a key factor in driving cell apoptosis (mitotic catastrophe) triggered by mitotic abnormalities, such as defects in chromosomes, mitotic spindles, or the cytokinesis apparatus 73,74 . Other genes within the list await functional validation.…”

Section: Discussionmentioning

confidence: 99%

Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery

Giotti

Chen

Barnett

et al. 2018

Preprint

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13The set of proteins required for mitotic division remains poorly characterised. Here, an 14 extensive series of correlation analyses of human and mouse transcriptomics data was 15 performed to identify genes strongly and reproducibly associated with cells undergoing S/G2-16M phases of the cell cycle. In so doing, a list of 701 cell cycle-associated genes was defined 17and shown that whilst many are only expressed during these phases, the expression of others 18 is also driven by alternative promoters. Of this list, 496 genes have known cell cycle functions, 19whereas 205 were assigned as putative cell cycle genes, 53 of which are functionally 20uncharacterised. Among these, 27 were screened for subcellular localisation revealing many 21to be nuclear localised and at least four to be novel centrosomal proteins. Furthermore, 10 22 others inhibited cell proliferation upon siRNA knockdown. This study presents the first 23comprehensive list of human cell cycle proteins, identifying many new candidate proteins. 24 33 are important therapeutic targets 3 and novel components might present new therapeutic 34opportunities. 36Many of the key proteins required for mitotic division are known from studies in model 37 organisms including yeast, as well as mammalian cells 4,5 . With the aim of identifying all the 38 components of the system, high content analysis platforms have been utilised. For example 39RNAi screens 6-8 , CRISPR/Cas9 9 , proteomics 10,11,12 studies have all proposed lists of cell cycle 40 genes/proteins but a consensus between studies has not emerged. In particular, genome-wide 41transcriptomics studies [13][14][15][16][17][18][19] have identified sets of transcripts sequentially regulated during 42 the cell cycle phases in multiple species but comparison of results from four studies of 43 different human cell lines identified only 96 genes in common 15 . Our reanalysis of these data, 44taking account of some of the technical variables, suggested that the true concordance of the 45 cell cycle transcriptional network across cell types is much greater 20 . Furthermore, our 46analyses of large collections of tissue and cell transcriptomics data commonly identify a large 47 cluster of cell cycle transcripts whose expression is elevated in cells or tissues with a high 48 mitotic index [21][22][23][24][25] . 49 50We report here on a data driven curation exercise aimed at identifying the cohort of genes 51up-regulated in all human cell types from the G1/S boundary through to the completion of M 52 phase (S/G2-M). There are of course, many growth-associated transcriptional regulatory 53 events including activation of cyclins, cyclin-dependent kinases and E2F transcription factors, 54 that occur during G1 and are a precondition for entry into S phase 26 , but these are not the 55 focus of this study. We monitored genome-wide gene expression in primary human dermal 56fibroblasts (NHDF) cells as they synchronously enter the cell cycle from a resting state (G0). 57Using network co-expression analysis and clustering of ...

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Section: Discussionmentioning

confidence: 99%

Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery

Giotti

Chen

Barnett

et al. 2018

Preprint

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“…Caspase-2 is one of the evolutionarily most conserved caspases, yet its function has remained enigmatic for a long time (15). More recently, accumulating evidence indicated an important role of caspase-2 in the maintenance of genomic stability (16). Caspase-2 can be activated by DNA damage, cell cycle dysregulation, and abnormal mitosis.…”

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confidence: 99%

Human cytomegalovirus glycoprotein B variants affect viral entry, cell fusion, and genome stability

Tang

Frascaroli

Lebbink

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Human cytomegalovirus (HCMV), like many other DNA viruses, can cause genome instability and activate a DNA damage response (DDR). Activation of ataxia-telangiectasia mutated (ATM), a kinase activated by DNA breaks, is a hallmark of the HCMV-induced DDR. Here we investigated the activation of caspase-2, an initiator caspase activated in response to DNA damage and supernumerary centrosomes. Of 7 HCMV strains tested, only strain AD169 activated caspase-2 in infected fibroblasts. Treatment with an ATM inhibitor or inactivation of PIDD or RAIDD inhibited caspase-2 activation, indicating that caspase-2 was activated by the PIDDosome. A set of chimeric HCMV strains was used to identify the genetic basis of this phenotype. Surprisingly, we found a single nucleotide polymorphism within the AD169 UL55 ORF, resulting in a D275Y amino acid exchange within glycoprotein B (gB), to be responsible for caspase-2 activation. As gB is an envelope glycoprotein required for fusion with host cell membranes, we tested whether gB(275Y) altered viral entry into fibroblasts. While entry of AD169 expressing gB(275D) proceeded slowly and could be blocked by a macropinocytosis inhibitor, entry of wild-type AD169 expressing gB(275Y) proceeded more rapidly, presumably by envelope fusion with the plasma membrane. Moreover, gB(275Y) caused the formation of syncytia with numerous centrosomes, suggesting that cell fusion triggered caspase-2 activation. These results suggest that gB variants with increased fusogenicity accelerate viral entry, cause cell fusion, and thereby compromise genome stability. They further suggest the ATM-PIDDosome-caspase-2 signaling axis alerts the cell of potentially dangerous cell fusion.

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“…Caspase-2 is described as a multifaceted enzyme, implicated in selected apoptotic signaling pathways, as well as in processes serving to avoid aneuploidy and tumorigenic cellular states 28 , 29 . In an unbiased experimental approach, aimed at detecting caspase-2 protein interactions, which could serve as further elucidation of molecular mechanisms that have been assigned to the enzyme, we performed a Y2H assay using a full-length caspase-2 wild-type construct as bait to screen a randomly primed human lung cancer cell line (A549, H1703, H460) cDNA library (83 million clones, 8-fold the complexity of the library).…”

Section: Resultsmentioning

confidence: 99%

A caspase-2-RFXANK interaction and its implication for MHC class II expression

Forsberg

Akpinar

et al. 2018

Cell Death Dis

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Despite recent achievements implicating caspase-2 in tumor suppression, the enzyme stands out from the apoptotic caspase family as a factor whose function requires further clarification. To specify enzyme characteristics through the definition of interacting proteins in apoptotic or non-apoptotic settings, a yeast 2-hybrid (Y2H) screen was performed using the full-length protein as bait. The current report describes the analysis of a captured prey and putative novel caspase-2 interacting factor, the regulatory factor X-associated ankyrin-containing protein (RFXANK), previously associated with CIITA, the transactivator regulating cell-type specificity and inducibility of MHC class II gene expression. The interaction between caspase-2 and RFXANK was verified by co-immunoprecipitations using both exogenous and endogenous proteins, where the latter approach suggested that binding of the components occurs in the cytoplasm. Cellular co-localization was confirmed by transfection of fluorescently conjugated proteins. Enhanced caspase-2 processing in RFXANK-overexpressing HEK293T cells treated with chemotherapeutic agents further supported Y2H data. Yet, no distinct differences with respect to MHC class II expression were observed in plasma membranes of antigen-presenting cells derived from wild type and caspase-2−/− mice. In contrast, increased levels of the total MHC class II protein was evident in protein lysates from caspase-2 RNAi-silenced leukemia cell lines and B-cells isolated from gene-targeted mice. Together, these data identify a novel caspase-2-interacting factor, RFXANK, and indicate a potential non-apoptotic role for the enzyme in the control of MHC class II gene regulation.

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Caspase-2: an orphan enzyme out of the shadows

Cited by 16 publications

References 51 publications

Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery

Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery

Human cytomegalovirus glycoprotein B variants affect viral entry, cell fusion, and genome stability

A caspase-2-RFXANK interaction and its implication for MHC class II expression

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