cells Review The Role of Caspase-2 in Regulating Cell Fate Vasanthy Vigneswara and Zubair Ahmed * Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK; [email protected] * Correspondence: [email protected] Received: 15 April 2020; Accepted: 12 May 2020; Published: 19 May 2020 Abstract: Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation of caspase-2 to mediate multiple cellular processes far beyond apoptotic cell death. This review provides a comprehensive overview of the literature pertaining to possible sophisticated molecular mechanisms underlying the multifaceted process of caspase-2 activation and to highlight its interplay between factors that promote or suppress apoptosis in a complicated regulatory network that determines the fate of a cell from its birth and throughout its life. Keywords: caspase-2; procaspase; apoptosis; splice variants; activation; intrinsic; extrinsic; neurons 1. Introduction Apoptosis, or programmed cell death (PCD), plays a pivotal role during embryonic development through to adulthood in multi-cellular organisms to eliminate excessive and potentially compromised cells under physiological conditions to maintain cellular homeostasis [1]. However, dysregulation of the apoptotic signaling pathway is implicated in a variety of pathological conditions. For example, excessive apoptosis can lead to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, whilst insufficient apoptosis results in cancer and autoimmune disorders [2,3]. Apoptosis is mediated by two well-known classical signaling pathways, namely the extrinsic or death receptor-dependent pathway and the intrinsic or mitochondria-dependent pathway. These two pathways can be activated independently or in combination, in response to either physiologically- or experimentally-induced death stimuli. The extrinsic apoptotic pathway is triggered by various extracellular death signals, whereas the intrinsic pathway is activated by intracellular damage, oxidative stress, and deprivation of growth factors [4–6]. Caspases, a family of cysteine aspartate proteases, orchestrate apoptotic activities in diverse organisms, including nematodes and mammals. [7–9]. Thus, the intracellular molecular mechanism underlying apoptosis is evolutionarily conserved across species. Based on the structural characteristics and the functional hierarchy, caspases are generally grouped into 3 categories: Group I are involved in inflammation, Group II are initiator caspases, whilst Group III are executioner caspases (Figure1). Caspases involved in PCD are categorized into two distinct groups: the long prodomain containing initiator caspases including caspases-2, -8 and -9, and the short prodomain possessing executioner or effector caspases-3, -6 and -7. The initiator or apical caspases act upstream of effector caspases, either directly or indirectly activated by cleavage with aspartate substrate specificity, and then the activated executioner caspases, in turn, cleave their respective cellular substrates to orderly demise compromised cells [5,10]. Among all the caspases, caspase-2, the second mammalian caspase to be characterized, is the most evolutionarily conserved caspase [11,12], suggesting that caspase-2 may play pivotal roles in maintaining the molecular and cellular integrity of an organism during development and throughout their lives. Cells 2020, 9, 1259; doi:10.3390/cells9051259 www.mdpi.com/journal/cells Cells 2020, 9, 1259 2 of 45 Cells 2020, 9, x FOR PEER REVIEW 2 of 46 FigureFigure 1. Structure1. Structure of of caspases. caspases. Three Three major major groupsgroups ofof caspasescaspases are shown. Group Group I: I: inflammatory inflammatory caspases;caspases; Group Group II: II: apoptosis apoptosis initiator initiator caspases; caspases; GroupGroup III:III: apoptosisapoptosis effector effector caspases. caspases. The The caspase caspase recruitmentrecruitment domain domain (CARD), (CARD), the the death death eeffectorffector domaindomain (DED), and and the the large large (p20) (p20) and and small small (p10) (p10) catalyticcatalytic subunits subunits are are indicated. indicated. * * Caspase-11 Caspase‐11 is only found found in in mouse mouse and and is ishomologous homologous to caspase to caspase-4.‐4. DespiteDespite its its early early discovery, discovery, retention, retention, and and conservation conservation of sequence sequence homology homology during during evolution, evolution, therethere has has been been a traditionala traditional concept concept that that caspase-2, caspase‐2, formerlyformerly known as as ICH ICH-1‐1 (pro (pro-interleukin‐interleukin convertingconverting enzyme enzyme homolog-1 homolog‐1 [ 13[13],], is is a a functionally functionally redundantredundant initiator caspase. caspase. The The gene gene for for caspase-2caspase was‐2 was initially initially identified identified during during hybridization hybridization screeningscreening for for mouse mouse genes, genes, which which were were highly highly expressedexpressed in neuralin neural precursor precursor cells, and cells, initially and termed initially Nedd2 termed (neuronally Nedd2 expressed (neuronally developmentally expressed downregulateddevelopmentally gene downregulated 2), as their respective gene 2), mRNA as their levels respective weredownregulated mRNA levels during weredownregulated the development of theduring brain the [ development14–16]. Nedd2 of the was brain subsequently [14–16]. Nedd2 shown was to subsequently be homologous shown to to the be homologousC. elegans death to gene-3the C. (CED-3). elegans death Developmental gene‐3 (CED downregulation‐3). Developmental of downregulation caspase-2 in the of adult caspase brain,‐2 in lack the ofadult an brain, explicit phenotypelack of an in explicit caspase-2 phenotype null mice in [caspase17,18],‐ the2 null failure mice of [17,18], the identification the failure of of the comparatively identification more of substratescomparatively of caspase-2 more [ 19substrates,20], and theof inadequatecaspase‐2 [19,20], new technologies and the inadequate to investigate new its distincttechnologies activation to pathwaysinvestigate to delineateits distinct itsactivation apoptotic pathways and non-apoptotic to delineate its functions apoptotic and [21] non are‐apoptotic major factors functions that [21] have are major factors that have hampered the identification of a clear functional role for caspase‐2. As a hampered the identification of a clear functional role for caspase-2. As a result, caspase-3 has received result, caspase‐3 has received considerably more attention than other caspases, owing to its considerably more attention than other caspases, owing to its inherently high abundance and catalytic inherently high abundance and catalytic efficiency [22,23]. efficiency [22,23]. However, caspase‐2 has functional complexity and a much broader context than initially However, caspase-2 has functional complexity and a much broader context than initially expected. expected. These studies have implicated the context‐dependent apoptotic function of caspase‐2 in Thesevarious studies cell have death implicated paradigms the and context-dependent its novel and previously apoptotic unidentified function of non caspase-2‐apoptotic in variousfunctions cell death[19,24–26]. paradigms In line and with its novel the recent and previouslydata, a previous unidentified study on non-apoptotic caspase‐2 already functions showed [19 that,24– caspase26]. In‐ line2 withhas the both recent positive data, and a previous negative studyregulatory on caspase-2 functions already in apoptosis showed depending that caspase-2 on the cell has type, both state positive of andgrowth, negative and regulatory death stimuli functions [17]. Hence, in apoptosis current dependingand future research on the cell studies type, must state take of growth, into account and death the stimuliimplications [17]. Hence, of therapeutic current and inhibition future researchof caspase studies‐2 activity must to take inhibit into cell account death theupon implications other non‐ of therapeuticapoptotic inhibitionfunctions of of caspase caspase-2‐2. 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