MINI REVIEW published: 10 January 2022 doi: 10.3389/fcell.2021.826037 FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic Caspase Function Elena Coccia 1,2,3†, Montse Solé 1,2,3 and Joan X Comella 1,2,3* 1 Edited by: Cell Signaling and Apoptosis Group, Vall d’Hebron Institute of Research (VHIR), Barcelona, Spain, 2Centro de Investigación Bertrand Joseph, Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain, 3Departament de Bioquímica I Karolinska Institutet (KI), Sweden Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain Reviewed by: Mohanish Deshmukh, Apoptosis is crucial for the correct development of the nervous system. In adulthood, the University of North Carolina at Chapel Hill, United States same protein machinery involved in programmed cell death can control neuronal *Correspondence: adaptiveness through modulation of synaptic pruning and synaptic plasticity Joan X Comella processes. Caspases are the main executioners in these molecular pathways, and Joan.comella@vhir.org their strict regulation is essential to perform neuronal remodeling preserving cell † Present Address: survival. FAIM-L and SIVA-1 are regulators of caspase activation. In this review we will Elena Coccia, Nash Family Department of focus on FAIM-L and SIVA-1 as two functional antagonists that modulate non-apoptotic Neuroscience, Icahn School of caspase activity in neurons. Their participation in long-term depression and neurite pruning Medicine at Mount Sinai, New York, NY, United States will be described in base of the latest studies performed. In addition, the association of Department of Neurology, FAIM-L non-apoptotic functions with the neurodegeneration process will be reviewed. Icahn School of Medicine at Mount Sinai, New York, NY, United States Keywords: synaptic plasticity (LTP/LTD), pruning, XIAP antagonist, axon remodeling, Alzheimer’s disease Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States INTRODUCTION Ronald M. Loeb Center for Alzheimer’s Disease, Neuronal apoptotic pathways play crucial roles during the nervous system development Icahn School of Medicine at Mount (Burek and Oppenheim, 1996) as selective elimination of those neurons that are unable to Sinai, New York, NY, United States correctly innervate their targets, ensuring the survival of complete and functional circuits only. Black Family Stem Cell Institute, Icahn School of Medicine at Mount We have an extensive knowledge of the pathways that lead to apoptosis. Caspases are the main Sinai, New York, NY, United States executioners of apoptosis, and for years their role orchestrating programmed cell death has been broadly reported in physiology and pathology of the nervous system (Lossi et al., 2018; Specialty section: Hollville et al., 2019; Voss and Strasser, 2020). This article was submitted to During the last 2 decades, however, accumulating evidence has been supporting a non-apoptotic Signaling, and non-inflammatory function of caspases in neurons, essential in processes that occur during the a section of the journal whole life of the organism, as dendritic pruning and synaptic plasticity. Overall, caspases emerge as Frontiers in Cell and Developmental decisive in every structural change of the nervous system beyond apoptosis, starting from Biology development, remodeling, and finally degeneration (D’Amelio et al., 2011; Hyman, 2011; Unsain Received: 30 November 2021 et al., 2013; Mukherjee and Williams, 2017). Accepted: 20 December 2021 In the non-apoptotic processes as pruning it has been shown that while active caspases are found Published: 10 January 2022 in degenerating axons, the cell bodies remain viable (Williams et al., 2006; Simon et al., 2016). To Citation: allow neuronal survival, caspase activation is required to be transient and localized to specific cell Coccia E, Solé M and Comella JX compartments, such as neurites during pruning upon nerve growth factor (NGF) deprivation or (2022) FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic nerve injury (Simon et al., 2012; Unsain et al., 2013; Yang et al., 2013), or synapses during plasticity Caspase Function. processes (Hollville and Deshmukh, 2018). Different levels of control can limit caspase to sublethal Front. Cell Dev. Biol. 9:826037. activation conditions, such as specific and a rapid turnover of proteins that modulate caspase doi: 10.3389/fcell.2021.826037 activation (Jiao and Li, 2011; Simon et al., 2016). Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 January 2022 | Volume 9 | Article 826037 Coccia et al. FAIM-L/SIVA-1 in Neuronal Plasticity Here we will review FAIM-L and SIVA-1, two proteins FAIM-L and SIVA-1 in Non-Apoptotic Roles involved in the complex molecular interplay that regulates of Caspases caspase activation which our group has shown to be Many forms of learning and memory require experience- functional antagonists on caspase-activation and consequent dependent synaptic adjustments in the hippocampus (Bateup functions in neurons. and Sabatini, 2010). The best characterized forms of long-term plasticity of excitatory synapses in response to glutamate signaling are long-term potentiation (LTP) and depression FAIM-L and SIVA-1 as Components of the (LTD). In LTP the outcome is a gain in AMPA receptor Classic Apoptotic Pathway (AMPAR) expression and increase in synaptic strength, while The first Fas apoptotic Inhibitory Molecule gene product, in LTD, synapses experience a decrease in the number of surface FAIM-short (FAIM-S), was identified as a death receptor AMPA receptors and weakening of synapses (Beattie et al., 2000). (DR) inhibitor in immune cells (Schneider et al., 1999). Few Studies have shown a great conservation between apoptotic and years later, a neuronal-specific isoform, FAIM-long (FAIM- LTD induction pathways. During LTD it has been shown the L) was described (Zhong et al., 2001). FAIM-S is ubiquitously activation of essential players of the apoptotic pathway, expressed and is capable of inducing resistance to Fas- mitochondrial engagement, and cytochrome-c release. mediated cell death in several cell types (Schneider et al., Caspase-3 is found to be the essential effector of LTD, which, 1999; Sole et al., 2004; Kaku and Rothstein, 2010). in fact, is abolished in the hippocampus of caspase-3 deficient Remarkably, in neurons, FAIM-S does not directly protect mice (Li et al., 2010). from DR-induced apoptosis, but it has a role in promoting During recent years several modulators of apoptosis have been NGF-dependent neuronal differentiation and branching implicated in LTD regulation. Our group has shown that both through activation of ERK and NF-κB pathways (Sole FAIM-L and SIVA-1 are able to play a role in AMPAR et al., 2004). FAIM-L on the other hand, is expressed internalization, but with opposite roles (Figure 1). In our exclusively in neurons and differs from FAIM-S by the studies we used the extensively described chemical LTD inclusion of the neuronal exon 2b, which codifies for 22 aa (chLTD) (Li et al., 2004), in which primary neurons undergo located at the N-Term of the protein (Segura et al., 2007; LTD changes after cells are trated with NMDA for a short Coccia et al., 2017). Our group has focused on elucidating treatment (15min). That is, with NMDA stimulation, chLTD FAIM-L mechanism of action, and over the years we have is induced. A rapid increase in calcium levels is triggered by been able to describe part of its relevance in neurons. NMDA receptor activation, followed by calcineurin activation. FAIM-L blocks DR-induced cell death by two main Calcineurin dephosphorylates AMPAR and pBAD, which in turn mechanisms: direct binding to non-stimulated Fas receptor, leads to activation of apoptotic-machinery components and therefore impairing caspase-8 recruitment to the DISC finally caspase-3. The activation of caspase-3 culminates in complex (Segura et al., 2007), and acting on the regulation of AMPAR internalization and therefore synaptic weakening (Lee XIAP degradation, the main endogenous inhibitor of effector et al., 1998, 2002; Li et al., 2010; Jiao and Li, 2011). In 2016 we caspases. FAIM-L can directly bind to XIAP’s BIR2 domain and demonstrated that FAIM-L overexpression totally abrogates impair its auto-ubiquitination and consequent degradation by the AMPAR internalization in LTD through stabilization of XIAP proteasome. Therefore, FAIM-L maintains XIAP levels, enabling and consequent caspase-3 inhibition (Martínez-Mármol et al., it to inhibit effector caspases and to promote survival (Moubarak 2016). et al., 2013). SIVA-1 on the other hand has the opposite effect, as its As part of FAIM-L characterization we were able to identify overexpression is sufficient to decrease GluA2 levels, a SIVA-1 as an interacting partner (Coccia et al., 2020). SIVA-1 was component of AMPAR, in a caspase-dependent manner. first described in 1997 in immune cells as an adaptor protein that FAIM-L restores AMPAR levels changes induced by SIVA-1 binds to the cytoplasmic tail of CD27 receptor (Prasad et al., in hippocampal neurons, indicating that both proteins act on 1997), and has been later found to also interact and modulate the same pathway. signal transduction of different TNFR family receptors (Spinicelli Another non-apoptotic mechanism in which apoptotic et al., 2002). SIVA-1 has been described to induce extensive proteins are essential is neurite pruning, essential to sculpt apoptosis through multiple mechanisms (Cao et al., 2001; Py neuronal connections, as it removes excessive or inaccurate et al., 2004, 2007; Zins et al., 2014). Several typical markers have projections without resulting in the death of the cell. The been reported in SIVA-1 cell death induction, such as BAK/BAX mechanism can involve small-scale pruning of axon terminals, translocation to mitochondrial membrane, cytochrome-c release or large-scale removal of branches (Luo and O’Leary, 2005). and caspase-3 activation (Xue et al., 2002; Jacobs et al., 2007; Pruning is characterized by cytoskeletal destabilization, Resch et al., 2009). Moreover, SIVA-1 is an inhibitor and microtubules disassemble, neurofilament fragmentation and interacting partner of XIAP (Resch et al., 2009; Coccia et al., degradation of axonal components. The portion of the axon 2020). In our recent work we demonstrated that SIVA-1 induces destined for removal is finally engulfed and digested by neuronal cell death through caspase-3 activation, and that it surrounding glia (Saxena and Caroni, 2007). displaces the FAIM-L/XIAP interaction, which can be During development of the peripheral nervous system, sufficient to promote XIAP degradation (Coccia et al., 2020). depriving of NGF only distal axons of neurons promotes axon Frontiers in Cell and Developmental Biology | www.frontiersin.org 2 January 2022 | Volume 9 | Article 826037 Coccia et al. FAIM-L/SIVA-1 in Neuronal Plasticity FIGURE 1 | Participation of FAIM-L and SIVA-1 in neuronal plasticity processes. The upper panel diagram represents the molecular mechanism by which FAIM-L and SIVA-1 are involved in AMPA receptors internalization during LTD processes in synaptic plasticity, in response to NMDA stimulation. The maintenance of XIAP-FAIM- L interaction would allow XIAP-mediated caspase-3 inhibition, and therefore prevent the caspase-3-dependent AMPA receptors internalization; a displacement of this interaction mediated by SIVA-1 binding to FAIM-L would allow the activation of caspase-3 and its consequent LTD induction and synaptic weakening. The lower panel diagram shows the similar role of FAIM-L and SIVA-1 in axonal pruning, as in trophic factors deprivation. In this case, an upstream activation of the mitochondrial apoptotic machinery would converge in the activation of caspase-3, whose activity would be regulated by the balance between SIVA-1-FAIM-L or XIAP-FAIM-L binding. pruning and remodeling without causing neuronal death machinery, and local mRNA (Williams et al., 2006; Ertürk et al., (Nikolaev et al., 2009; Cusack et al., 2013). In vitro culture of 2014). Mitochondria are essential for activating the pathway that peripheral sensory neurons is a convenient system to study this leads to caspase engagement in non-apoptotic activities. These process, and has been widely used as a model for developmental organelles can be found in dendrites, and sometimes in individual disease (Campenot, 1977). spines (Li et al., 2004). Moreover, their distribution and motility Experimental results show that in response to local NGF are regulated by synaptic activity, allowing for a spatial control of withdrawal, a pathway that converges with apoptotic initiation the pathway activation (Li et al., 2004). is activated. BAX engagement is required to induce cytochrome-c During plasticity processes it is essential to have a local and release from mitochondria (Nikolaev et al., 2009), and a caspase-9 rapid turnover of components of the synaptic proteome, to caspase-3 cascade is activated and crucial for apoptosis (Luo composed by ion channels, neurotransmitter receptors, and O’Leary, 2005; Buss et al., 2006). Caspase-3, the main regulators of synaptic function, and adhesion and scaffolding effector, activates caspase-6, which plays a significant but molecules. Synapses are equipped to have rapid and dynamic subsidiary downstream role (Simon et al., 2012). Caspases changes in protein levels necessary for plasticity. Both translation finally orchestrate cytoskeleton fragmentation and organelle machinery and proteasomal system are found in synapses, so that degradation. protein synthesis and degradation occurs rapidly and Several mechanisms fine-tune the activation intensity of independently of the cell Soma - that can be located up to caspase-3, thereby favoring a transient activity in LTD and hundreds of microns away (Schuman et al., 2006; Richter and pruning, instead of a persistent activation that would commit Klann, 2007; Tom Dieck et al., 2014). Like other pro-apoptotic cells to induce apoptosis. Proteins that participate in apoptotic proteins, SIVA-1 is involved in this process by maintaining a modulation are found in dendrites and synaptic terminals, which partial induction of caspase-3 activation. During LTD, pro- are also equipped with the tools for a rapid and strictly regulated apoptotic BAX and BAD have been shown to be sufficient and protein turnover, such as proteasome for degradation, translation necessary for mitochondrial factor release. However, as opposed Frontiers in Cell and Developmental Biology | www.frontiersin.org 3 January 2022 | Volume 9 | Article 826037 Coccia et al. FAIM-L/SIVA-1 in Neuronal Plasticity to apoptotic induction, in this situation BAX translocation to the described that memory loss, beginning early in AD, can be mitochondrial membrane is not observed, therefore resulting in attributed to processes previous to cell death. Aβ oligomers only a mild engagement of mitochondria that could explain the induce a deregulation of LTD, which causes disruption of transient activation of the apoptotic cascade (Li et al., 2010; Jiao synaptic plasticity, micro-pruning, and spine loss (Fasulo and Li, 2011). SIVA-1 regulation, on the other hand, is secured by et al., 2000; Gamblin et al., 2003; Rissman et al., 2004; a rapid calcium dependent induction, and its levels are Zhou et al., 2004; D’Amelio et al., 2011; Oh et al., 2013). maintained only for a few minutes after the stimulation Given that both FAIM-L and SIVA-1 are involved in these (Coccia et al., 2020). Synthesis of new proteins encoded by pathways, any deregulation of their functional balance can be pre-existing mRNAs in the synapses occurs in response to determinant for assessing the progression or a potential stimulation, and even if it is not necessary for initiation of treatment of the disease. AMPAR endocytosis in hippocampal LTD, it is required for Recently, a relationship between FAIM and protein AMPAR trafficking for its maintenance (Huang et al., 2005; aggregation became evident (Kaku et al., 2020) pointing to Hoeffer and Klann, 2008; Di Prisco et al., 2014). a function of FAIM in protein homeostasis. FAIM is able to FAIM-L also recently emerged as a regulator of caspase- protect against environmental insults that cause dependent non-apoptotic activation during long-term accumulation of cytotoxic and aggregated proteins, such as synaptic depression (LTD) and neurite pruning (Martínez- oxidative stress, which are frequently found in the main Mármol et al., 2016). As other anti-apoptotic proteins such as neurodegenerative diseases. The protective mechanism in XIAP and BCL-2, FAIM-L has a crucial role in temporal and this case is reported to be caspase-independent and based spatial restriction of the physiological activation of caspases on the ability to bind to ubiquitinated protein aggregates and to local sites and to suppress it so that it does not spread to the prevent cell damage. Both FAIM-S and FAIM-L prevent Aβ whole cell (Bateup and Sabatini, 2010; Li et al., 2010; aggregation in vitro. Therefore, FAIM-L decrease in AD could Martínez-Mármol et al., 2016). Specifically, IAPs (XIAP also be pathologically linked to a more rapid, aggressive Aβ protein family) can bind to caspases in a sort of IAP-based aggregation. In a Faim-KO mice model (Huo et al., 2016), we “clutch system,” in which active caspases are stalled, ready for identified the presence of ubiquitinated aggregates quick release upon stimuli, bypassing the need for Apaf-1 and throughout the retina, a gliotic activation response in the apoptosome formation. Together, low Apaf1 engagement and Müller cells, and pronounced vascular leakage that lead to high FAIM-L levels grant a strict control of XIAP post- late-onset photoreceptor cell death (Sirés et al., 2021). cytochrome-c inhibition of caspases which allows to stop Beyond its role in apoptosis, SIVA-1 also regulates other the wave of caspase activation before it can reach cell Soma cellular processes, such as cellular migration (Li et al., 2011; (Potts et al., 2003; Martínez-Mármol et al., 2016). Ma et al., 2017), autophagy (Van Nostrand et al., 2015), and proliferation (Ma et al., 2017; Liu et al., 2020). In cancer studies FAIM-L and SIVA-1 in Pathologies SIVA-1 has been found to have a role as pro- or anti-malignant Our group has found a correlation between FAIM-L levels and factor, depending on cellular context (Vachtenheim et al., 2018). Alzheimer’s disease (AD) progression (Carriba and Comella, Studies carried out in ovarian and cervical cancer cells show 2015; Carriba et al., 2015). AD is the principal that SIVA-1 suppresses migration and invasion of cancer cells, neurodegenerative disease, whose main hallmarks are and overall prevents metastasis through phosphorylation of extracellular aggregates of amyloid beta (Aβ), intraneuronal stathmin, a microtubule destabilizer (Ma et al., 2017; Liu et al., Tau neurofibrillary tangles, and progressive neuronal loss. 2020). FAIM-L decrease is induced by Aβ oligomers in culture, and In other cases, instead, SIVA-1 has been reported to have it would imply a higher susceptibility to stress insults to neurons. the opposite role. Pro-oncogenic role of SIVA-1 has been Moreover, since FAIM-L and SIVA-1 counteract each other’s linked to a negative feedback loop regulation that can induce function, loss of FAIM-L would induce a gain of function of degradation of p53 (Wang et al., 2013), and to its SIVA-1 activity, and overall, a deregulation of the pathways that involvement in mitochondrial respiratory capacity and lead to caspase activation. energy production. Van Nostrand and others showed in Over-activation of caspases would afterwards exacerbate non-small cell lung cancer that SIVA-1 knockdown the hallmarks of AD, being first extreme plasticity processes reduces energy production and results in autophagy, in neurons, and finally neuronal degeneration (Chi et al., suggesting that SIVA-1 is necessary to facilitate 2018; Wang et al., 2020; Baranov et al., 2021). Hundreds of tumorogenesis (Van Nostrand et al., 2015). studies can be found on the correlation among caspase In line with the findings of SIVA-1 as a protein of relevance in activation and AD pathological markers, such as increase several cellular processes, Jacobs and others reported an essential in production of Aβ (Unsain and Barker, 2015), microtubule role of SIVA-1 during embryonic development, during which a associated protein tau phosphorylation and aggregation (Wu tight regulation of cellular proliferation and differentiation et al., 2010), and as consequence, to deficits in cell survival mechanisms is essential. They generated a Siva-1 KO mice and and plasticity pathways. Mouse models of the disease, which reported that Siva-1 deficiency results in mid-gestational overexpress human amyloid precursor protein (APP), have embryonic lethality, associated with several developmental been extremely useful to detect which pathways are abnormalities, developmental delay and defects in neural tube deregulated in the disease. Thanks to these models, it was closure (Jacobs et al., 2019). Frontiers in Cell and Developmental Biology | www.frontiersin.org 4 January 2022 | Volume 9 | Article 826037 Coccia et al. FAIM-L/SIVA-1 in Neuronal Plasticity Available Mouse Models to Study FAIM FAIM-S. For this reason, it would be of great interest to generate For many FAIM-related functions it is not clear which isoform of new specific mouse models knockout of each FAIM isoform, and FAIM (L or S) is responsible for the observed effects. Currently more interestingly of FAIM-L because of its selective expression available Faim-KO models lack both forms of the protein, and in neuronal cells and relevance in cell-type specific physiology. some inconsistency is found in the reports about Faim-KO mice phenotypes. Dr. Lam’s group reported FAIM-S regulation of insulin signaling and first generated a FAIM null mouse in CONCLUSION 2009 (Huo et al., 2009). These mice present a spontaneous non-hyperphagic obesity, an increased fatty acid synthesis in In conclusion, we have reviewed the role of FAIM-L and SIVA-1 the liver, and reduced insulin receptor beta, supporting the as novel regulatory proteins that modulate the activity of caspase- involvement of FAIM-S in energy homeostasis and insulin 3, involved in a wide range of remodeling processes that are signaling (Huo et al., 2016). The obese phenotype described by essential for a correct neuronal function. Given the relevance of Lam’s group was not reproduced in a second Faim-KO mice this fine-tune regulation, any alteration in regulatory proteins generated by Dr. Rothstein’s group (Kaku and Rothstein, 2020), may be a possible cause of pathology, and may constitute and in our study with the former model some phenotypic therefore, a plausible therapeutic target. A better characteristics changed based on the genetic background of understanding of the mechanisms involved in synapses the mice strain used. However, our group recently identified a remodeling will help the development of new therapeutic retinal neurodegenerative phenotype in Dr. Huo’s model, strategies for neurodegenerative diseases. compatible with the observations on protein homeostasis reported by Dr. Rothstein (Sirés et al., 2021). Several factors can influence the appearance of phenotypes when analyzing mice AUTHOR CONTRIBUTIONS models, such as genetic background of mice strain, flanking genes modifications during the generation of the mice, KO generation EC, MS, and JXC contributed to conception and design of the methodology, or environmental factors. The discrepancy on review. EC wrote the first draft of the manuscript. MS wrote reports about Faim-KO mice makes therefore difficult for us sections of the manuscript. All authors contributed to manuscript to appoint any phenotype described to the lack of FAIM-L or revision, read, and approved the submitted version. Coccia, E., Calleja-Yagüe, I., Planells-Ferrer, L., Sanuy, B., Sanz, B., López-Soriano, REFERENCES J., et al. (2017). Identification and Characterization of New Isoforms of Human Fas Apoptotic Inhibitory Molecule (FAIM). PLoS ONE 12, e0185327. Baranov, S. V., Jauhari, A., Carlisle, D. L., and Friedlander, R. M. (2021). 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