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Neuronal Function and Dysfunction of CYFIP2: from Actin Dynamics to Early Infantile Epileptic Encephalopathy

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Neuronal Function and Dysfunction of CYFIP2: from Actin Dynamics to Early Infantile Epileptic Encephalopathy BMB Rep. 2019; 52(5): 304-311 BMB www.bmbreports.org Reports Invited Mini Review Neuronal function and dysfunction of CYFIP2: from actin dynamics to early infantile epileptic encephalopathy Yinhua Zhang1,2, Yeunkum Lee1,2 & Kihoon Han1,2,* Departments of 1Neuroscience, 2Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Korea The cytoplasmic FMR1-interacting protein family (CYFIP1 and mutations of genes encoding key regulators of the neuronal CYFIP2) are evolutionarily conserved proteins originally actin cytoskeleton have been associated with numerous identified as binding partners of the fragile X mental neurodevelopmental and neuropsychiatric disorders, such as retardation protein (FMRP), a messenger RNA (mRNA)-binding autism spectrum disorders (ASDs), intellectual disability (ID), protein whose loss causes the fragile X syndrome. Moreover, schizophrenia (SCZ), and bipolar disorder (4-6). Among the CYFIP is a key component of the heteropentameric WAVE key regulators, the WAVE regulatory complex (WRC) is a regulatory complex (WRC), a critical regulator of neuronal ∼400 kDa heteropentameric protein complex consisting of actin dynamics. Therefore, CYFIP may play key roles in the Wiskott–Aldrich syndrome protein family verprolin- regulating both mRNA translation and actin polymerization, homologous protein (WAVE), cytoplasmic FMR1-interacting which are critically involved in proper neuronal development protein (CYFIP), Nck-associated protein (NAP), Abelson- and function. Nevertheless, compared to CYFIP1, neuronal interacting protein (ABI), and hematopoietic stem progenitor function and dysfunction of CYFIP2 remain largely unknown, cell 300 (HSPC300) (7, 8). The WRC is basally inactive toward possibly due to the relatively less well established association its downstream actin-nucleator, i.e., the actin-related protein between CYFIP2 and brain disorders. Despite high amino acid 2/3 (Arp2/3) complex, because the activity-bearing C-terminal sequence homology between CYFIP1 and CYFIP2, several in VCA (verprolin homology, central, and acidic regions) domain vitro and animal model studies have suggested that CYFIP2 of WAVE is sequestered by an intermolecular interaction with has some unique neuronal functions distinct from those of CYFIP (8). However, diverse cellular signaling can release the CYFIP1. Furthermore, recent whole-exome sequencing studies VCA domain from the CYFIP, enabling it to bind to and identified de novo hot spot variants of CYFIP2 in patients with activate the Arp2/3 complex. Specifically, inositol phospholipids early infantile epileptic encephalopathy (EIEE), clearly and the active form of the small GTPase Rac1 (Rac1-GTP) can implicating CYFIP2 dysfunction in neurological disorders. In cooperatively recruit the WRC to the plasma membrane and this review, we highlight these recent investigations into the induce its conformational changes (8). Considering that neuronal function and dysfunction of CYFIP2, and also discuss Rac1-GTP directly binds to the CYFIP during the activation several key questions remaining about this intriguing neuronal process, CYFIP is involved in both basal inhibition and protein. [BMB Reports 2019; 52(5): 304-311] Rac1-induced activation of the WRC. Furthermore, phosphorylation of several residues of WAVE, CYFIP, and ABI can also modulate the WRC activity (9-11). INTRODUCTION Two evolutionarily highly conserved members of the CYFIP gene family, namely CYFIP1 and CYFIP2 (also referred to as Actin cytoskeleton dynamics are critically involved in various SRA-1 and PIR121, respectively) exist (12). They are ∼145 aspects of neuronal development and function, including early kDa proteins, with a high homology in their amino acid migration, dendritic and axonal outgrowth and branching, and sequences (88% identity and 95% similarity), suggesting synapse formation and plasticity (1-3). Consistently, several similar functions at the molecular level. Originally, the CYFIP1/2 proteins were identified as binding partners of the *Corresponding author. Tel: +82-2-2286-1390; Fax: +82-2-953-6095; fragile X mental retardation protein (FMRP) (12), whose loss E-mail: [email protected] causes the fragile X syndrome (FXS), which is characterized by ID, autistic behaviors, and dysmorphic features (13). Indeed, in https://doi.org/10.5483/BMBRep.2019.52.5.097 addition to the WRC, CYFIP1 forms a complex with both the FMRP and the eukaryotic initiation factor 4E (eIF4E) to regulate Received 10 December 2018 the translational initiation of target messenger RNAs (mRNAs) (14). Notably, the brain-derived neurotrophic factor (BDNF)- Keywords: Actin polymerization, Cytoplasmic FMR1-interacting protein 2 (CYFIP2), Early infantile epileptic encephalopathy induced activation of Rac1 has been shown to redistribute (EIEE), Neuronal synapse, WAVE regulatory complex (WRC) CYFIP1 from the FMRP-eIF4E complex to the WRC, thereby ISSN: 1976-670X (electronic edition) Copyright ⓒ 2019 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/li- censes/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Neuronal function and dysfunction of CYFIP2 Yinhua Zhang, et al. orchestrating both activity-dependent local protein synthesis effects of Cyfip1, but not of Cyfip2, haploinsufficiency (in and actin remodeling in neuronal synapses (15). Clinically, Cyfip1＋/− mice) on both hippocampal dendritic spine density structural abnormalities (deletions and duplications) of the and morphology were explored, and an increase in immature chromosomal region (15q11-q13) encompassing CYFIP1 were long and thin spines compared to wild-type (WT) mice was identified in patients with ASDs and ID (16). CYFIP1 has also observed. been associated with SCZ (17). Furthermore, several lines of A large-scale in vivo phospho-proteomic analysis of nine Cyfip1 mutant mice expressed abnormal synaptic morphology mouse tissues (32) identified two brain-specific phosphory- and function, as well as either FXS- or ASD-like behaviors lation sites (S582 and T1067) of CYFIP2 (11). Furthermore, Lee (18-20). et al. overexpressed WT, phospho-blocking (i.e., S582A and In contrast to CYFIP1, the neuronal function and dysfunction T1067A), and phospho-mimetic (i.e., S582D and T1067E) of CYFIP2 remain largely unknown, possibly given the mutants of CYFIP2 in cultured hippocampal neurons to relatively less well established association between CYFIP2 understand functional significance of such sites (11). With and brain disorders thus far (16). Nevertheless, despite the regard to dendritic spine regulation, overexpression of the high sequence homology between CYFIP1 and CYFIP2, T1067A mutant, but not that of either WT or other mutants, several lines of evidence suggest that they may have distinct decreased the presence of stubby spines compared to control functions in vivo. For example, both Cyfip1 and Cyfip2 null neurons, suggesting a dominant-negative effect of T1067A. In mice display lethality at different developmental time points addition, while overexpression of WT CYFIP2 increased (i.e., at early embryonic and perinatal stages, respectively) neurite outgrowth, the same was not true for T1067A. (20-23). Furthermore, recent whole-exome sequencing (WES) Intriguingly, when mapped on the crystal structure of the WRC studies identified de novo hot spot mutations of CYFIP2 in (31), CYFIP2 T1067 was positioned at the interaction interface patients with early infantile epileptic encephalopathy (EIEE) between the CYFIP and the NAP, and T1067 phosphorylation (24, 25). In this review, we highlight recent in vitro, animal was predicted to weaken such an interaction (11). Lee et al. model, and human genetic investigations revealing the proposed a model based on these findings. It described that neuronal function and dysfunction of CYFIP2, and discuss the CYFIP2 T1067 phosphorylation, together with additional key remaining issues for a better understanding of this modifications of the WRC (such as bindings of inositol intriguing, yet largely uncharacterized, protein in the nervous phospholipids and Rac1-GTP (8)), contributed to WRC system. activation through the disassembling of the self-inhibitory interactions among its components (11). In contrast to T1067 IN VITRO NEURONAL STUDIES phosphorylation, the functional roles of CYFIP2 S582 phosphorylation, which is known to occur on the N-terminal Through the overexpression of green fluorescent protein outer surface of CYFIP2 in the WRC, are yet to be defined (11). (GFP)-tagged CYFIP1 and CYFIP2, Pathania et al. investigated the subcellular localization of these proteins in cultured rat ANIMAL MODEL STUDIES hippocampal neurons (26). Both CYFIP1-GFP and CYFIP2-GFP exhibited punctate clusters highly localized to the dendritic The in vivo neuronal functions of CYFIP were initially spines, which are small protrusions on the neuronal dendrites characterized in the Drosophila, which expresses only one representing excitatory postsynaptic compartments in mature homolog of CYFIP (dCYFIP) (16). In fact, Schenck et al. neurons (27). Consistently, both proteins co-localized with demonstrated that CYFIP is specifically expressed in the endogenous excitatory synaptic markers, namely the Homer central nervous system (CNS) of Drosophila, and is localized protein homolog (Homer) and the vesicular
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