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The Resurrection of the Piddosome – Emerging Roles in the DNA-Damage Response and Centrosome Surveillance Valentina Sladky1,*, Fabian Schuler1,*, Luca L

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The Resurrection of the Piddosome – Emerging Roles in the DNA-Damage Response and Centrosome Surveillance Valentina Sladky1,*, Fabian Schuler1,*, Luca L © 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 3779-3787 doi:10.1242/jcs.203448 REVIEW The resurrection of the PIDDosome – emerging roles in the DNA-damage response and centrosome surveillance Valentina Sladky1,*, Fabian Schuler1,*, Luca L. Fava1,2 and Andreas Villunger1,‡ ABSTRACT cellular physiology and aim to reconcile some of the remaining The PIDDosome is often used as the alias for a multi-protein complex controversy that surrounds the PIDDosome, first described as a that includes the p53-induced death domain protein 1 (PIDD1), the mediator of cell death in the DNA-damage response, containing bipartite linker protein CRADD (also known as RAIDD) and the pro- PIDD1, CASP2- and RIPK1-domain-containing adaptor with death form of an endopeptidase belonging to the caspase family, i.e. domain (CRADD, hereafter referred to as RAIDD) and CASP2 caspase-2. Yet, PIDD1 variants can also interact with a number of (Bock et al., 2012; Janssens and Tinel, 2012). other proteins that include RIPK1 (also known as RIP1) and IKBKG (also known as NEMO), PCNA and RFC5, as well as nucleolar The discovery of PIDD1 components such as NPM1 or NCL. This promiscuity in protein The official nomenclature for PIDD is now PIDD1 (p53-induced binding is facilitated mainly by autoprocessing of the full-length death domain protein 1). This was deemed necessary to avoid protein into various fragments that contain different structural confusion with primary immune deficiency disorders, often domains. As a result, multiple responses can be mediated by abbreviated the same way in the literature. Please note that there protein complexes that contain a PIDD1 domain. This suggests that are no reported PIDD1 orthologues in non-vertebrates, neither have PIDD1 acts as an integrator for multiple types of stress that need PIDD1 paralogues been found in vertebrates. PIDD1 was originally instant attention. Examples are various types of DNA lesion but also also known as leucine-rich repeat and death-domain-containing the presence of extra centrosomes that can foster aneuploidy and, protein (LRDD) and had been independently described by two ultimately, promote DNA damage. Here, we review the role of PIDD1 groups in the year 2000 (Telliez et al., 2000; Lin et al., 2000). In a in response to DNA damage and also highlight novel functions of bioinformatics screen for proteins containing a death domain PIDD1, such as in centrosome surveillance and scheduled (Box 1) similar to the one found in human receptor-interacting polyploidisation as part of a cellular differentiation program during serine/threonine kinase 1 (RIPK1, hereafter referred to as RIP1), organogenesis. Telliez et al. identified a protein and named it, according to its structural features, LRDD (Telliez et al., 2000). The characterisation KEY WORDS: Apoptosis, Caspase-2, Centrosomes, PIDD1, p53 of its sequence revealed leucine-rich repeats (LRRs) at the N- terminus, ZU5 domains (i.e. domains present in ZO-1 and Unc5- Introduction like netrin receptors) in the intermediate region, as well as a death The PIDDosome was described in 2004 by Antoine Tinel and the domain (DD) at the C-terminal end (Fig. 1A-C). Another structural late Jürg Tschopp, who spearheaded research in the field of cell domain called uncharacterised protein domain in UNC5, PIDD and death and inflammation for many years. Their initial findings ankyrins (UPA) was later defined between the ZU5 and the DD provided evidence for a long-sought function of a highly conserved (Wang et al., 2009). Moreover, the authors observed evidence for member of the caspase family caspase-2 (CASP2) as a cell death processing of PIDD1 as they detected truncated forms of the protein effector in the DNA-damage response (Tinel and Tschopp, 2004). in mammalian cells when overexpressing LRDD cDNA. Based on Yet, after a short period of excitement, interest in the PIDDosome as structural features, they speculated that LRDD functions as an a regulator of CASP2 ceased. This was mostly because of the lack of adapter for small G-proteins that had been shown to interact with phenotypes in mice depleted of individual PIDDosome components LRR sequences (Telliez et al., 2000). (Berube et al., 2005; Kim et al., 2009; Manzl et al., 2009; O’Reilly Lin and colleagues identified PIDD1 as a direct transcriptional et al., 2002); further, CASP2 could still become activated in the target of p53 by differential display analysis in an erythroleukemia absence of p53-induced death domain protein 1 (PIDD1), e.g. in cell cell line (Lin et al., 2000). Consistently, the sequence of the Pidd1 extracts in vitro, but also in dying neurons (Manzl et al., 2009; Ribe gene locus contained a non-canonical p53-responsive element in the et al., 2012). As the biology of CASP2 has been extensively Pidd1 promoter and upon γ-irradiation of mouse embryonic reviewed elsewhere (Bouchier-Hayes and Green, 2012; Fava et al., fibroblasts its mRNA was induced at the transcriptional level in a 2012; Puccini et al., 2013), it will not be the focus of this review. p53-dependent manner to an extent similar to that of cyclin- Here, we aim to give an overview on the biology of PIDD1. We dependent kinase inhibitor 1 (p21, officially known as CDKN1A). discuss potential roles in DNA damage, inflammation and normal Similar findings were made in MCF7 breast cancer and AML-4 leukaemia cells (Lin et al., 2000). Also, overexpression of PIDD1 suppressed cell growth by inducing apoptosis in p53-deficient cells, 1Division of Developmental Immunology, Biocenter, Medical University of and this effect was reversed by PIDD1 knockdown; PIDD1 was, Innsbruck, Innrain 80, 6020 Innsbruck, Austria. 2Center for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Povo, Italy. thus, assumed to be an essential component of the apoptotic arm of *These authors contributed equally to this work p53 (Lin et al., 2000). Around the same time, alternative cell death regulators that are induced by p53, such as phorbol-12-myristate- ‡Author for correspondence ([email protected]) 13-acetate-induced protein 1 (PMAIP1, hereafter referred to as A.V., 0000-0001-8259-4153 NOXA) (Oda et al., 2000) and Bcl-2-binding component 3 (BBC3, Journal of Cell Science 3779 REVIEW Journal of Cell Science (2017) 130, 3779-3787 doi:10.1242/jcs.203448 difficult to scrutinize which PIDD1 isoforms are expressed in a Box 1. Death domain proteins given cell type at protein level. Proteins that contain a death domain (DD), such as PIDD1, are PIDD1 autoprocessing requires binding of the chaperone heat characterised by a structural motif that contains six α-helical bundles shock protein 90 (Hsp90) and the co-chaperone p23 to facilitate the that make up a so-called ‘death fold’. This tertiary structure is also found optimal conformation needed for self-cleavage (Table 1). Hsp90 in other proteins that harbour either a caspase-recruitment domain interacts directly with FL-PIDD1 and recruits p23, a HSP90 co- (CARD), a death effector domain (DED), a pyrin domain (PYD) or, sometimes, a combination of such motifs (DD/CARD; DD/DED; PYRIN/ chaperone (Weaver et al., 2000; Tinel et al., 2011). Yet, another heat CARD), which links different death fold proteins with each other. Death shock protein, Hsp70, binds FL-PIDD1 as well as PIDD-N and folds generally allow for homotypic protein−protein interactions (DD/DD; PIDD-C; however, the role of this interaction remains to be CARD/CARD) that foster assembly of large multi-protein signalling investigated. Alongside autoproteolysis, the stability and function of complexes. Examples are the apoptotic protease-activating factor 1 PIDD1 also depends on Hsp90, which indicates an essential role for − (APAF1) caspase-9-containing apoptosome (i.e. a large quaternary chaperones in the regulation of PIDD1 self-processing and its protein structure that is formed during apoptosis), the caspase-8- containing death-inducing signalling complex (DISC) that comprises protein abundance (Table 1). Inhibition of Hsp90 allows rapid members of the tumour necrosis factor receptor (TNFR) superfamily degradation of PIDD1 by the E3 ubiquitin-protein ligase CHIP (also (Langlais et al., 2015), or different inflammasomes (i.e. oligomers known as STUB1), another co-chaperone that appears to comprising CASP1, PYCARD, NRLPs and sometimes CASP5), that preferentially ubiquitylate PIDD-C over PIDD-CC (Tinel et al., control activation of caspase-1 (Lamkanfi and Dixit, 2014). Common to 2011). CHIP directly interacts with PIDD1, but also with Hsp70, all these complexes is that they are engaged in response to different which might explain the role of Hsp70 in the regulation of PIDD1. developmental or environmental cues to control cell death and inflammatory responses, a feature conserved from invertebrates to Although the PIDDosome can form upon a temperature shift in vitro mammals. and dissociation of HSP90 is needed for its formation, the initial binding appears to be required for PIDD1 function: disruption of the interaction of Hsp90 with PIDD1 impairs its autoprocessing and binding to different effector proteins (Tinel et al., 2011). Yet, it is hereafter referred to as PUMA) (Han et al., 2001; Nakano and tempting to speculate that these effects are secondary to impaired Vousden, 2001; Yu et al., 2001), BH3-only members of the B-cell PIDD1 autoprocessing when Hsp90 is absent. Given the complex CLL/Lymphoma 2 (BCL2) family, were also described. Notably, regulation of the autoprocessing mechanism and the stability of subsequent loss-of-function analyses in mice confirmed roles for PIDD1, we anticipate that the stoichiometry and localisation of these two BH3-only proteins in the regulation of p53-induced cell protein complexes that contain PIDD1 domains are tightly regulated death; however, they failed to provide equally compelling evidence in order to elicit the desired biological response. for a role for PIDD1 in this process (Kim et al., 2009; Manzl et al., 2009; Shibue et al., 2003; Villunger et al., 2003).
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