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The DISC1–Girdin Complex – a Missing Link in Signaling to the T Cell Cytoskeleton

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The DISC1–Girdin Complex – a Missing Link in Signaling to the T Cell Cytoskeleton © 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs242875. doi:10.1242/jcs.242875 RESEARCH ARTICLE The DISC1–Girdin complex – a missing link in signaling to the T cell cytoskeleton Nicholas Maskalenko1, Shubhankar Nath2, Adarsh Ramakrishnan1, Nadia Anikeeva3, Yuri Sykulev3 and Martin Poenie1,* ABSTRACT alpha-L). Finally, there is the outermost zone known as the distal In this study, using Jurkat cells, we show that DISC1 (disrupted in supramolecular activation cluster (dSMAC), which is enriched in schizophrenia 1) and Girdin (girders of actin filament) are essential for lamellipodial actin (Freiberg et al., 2002). typical actin accumulation at the immunological synapse. Furthermore, One of the prominent features of the immunological synapse is the DISC1, Girdin and dynein are bound in a complex. Although this accumulation of actin, which is seen as a ring-like structure that forms complex initially forms as a central patch at the synapse, it relocates to a at the edges of the cell lamellae as they spread over the target cell. The peripheral ring corresponding to the peripheral supramolecular most obvious actin assembly at the synapse is thought to be triggered activation cluster (pSMAC). In the absence of DISC1, the classic by formation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), actin ring does not form, cell spreading is blocked, and the dynein which in turn leads to activation of the WASP-family verprolin complex fails to relocate to the pSMAC. A similar effect is seen when homologous protein WAVE2 and the actin-related protein (ARP) 2/3 ’ Girdin is deleted. When cells are treated with inhibitors of actin structure (Le Floc h et al., 2013; Chen et al., 2017; Basu et al., 2016). polymerization, the dynein–NDE1 complex is lost from the synapse and However, recent studies have revealed a remarkable complexity to the the microtubule-organizing center fails to translocate, suggesting that regulation of actin, involving multiple actin regulators and nucleators ’ actin and dynein might be linked. Upon stimulation of T cell receptors, with a variety of effects on T cell functions (Le Floc hetal.,2013; DISC1 becomes associated with talin, which likely explains why the Kumari et al., 2015; Jankowska et al., 2018; Janssen et al., 2016; dynein complex colocalizes with the pSMAC. These results show that Comrie et al., 2015). Defects in proper actin assembly have been the DISC1–Girdin complex regulates actin accumulation, cell linked generally to immunodeficiency and autoimmune dysfunctions spreading and distribution of the dynein complex at the synapse. (Wickramarachchi et al., 2010). More specifically, actin dynamics have been linked to sustained T cell signaling, cell spreading, calcium This article has an associated First Person interview with the first author entry, formation of stable adhesions and target cell stimulated of the paper. secretion in cytotoxic T lymphocytes (CTLs) (Babich et al., 2012; Carisey et al., 2018; Nolz et al., 2006). KEY WORDS: DISC1, Girdin, Immunological synapse, Dynein, In this study, we introduce new players in the T cell actin schema, Actin dynamics Girdin (girders of actin filaments) and DISC1 (disrupted in schizophrenia 1). DISC1 is a scaffolding protein that, in addition INTRODUCTION to dynein, interacts with over 100 different proteins including those When T cells engage antigen-presenting cells they form a associated with centromeres, the cytoskeleton, cell signaling and specialized contact site known as the immunological synapse. neuronal synapses (Camargo et al., 2007; Chubb et al., 2008). We Classically, the synapse can be described in terms of concentric previously showed that DISC1 forms a complex with dynein, NDE1 zones of receptors, adhesion proteins and cytoskeletal elements (neurodevelopment protein 1, also known as nuclear distribution (Monks et al., 1998; Bunnell et al., 2001; Kupfer et al., 1987; protein nudE homolog 1) and LIS1 (lissencephaly 1) in Jurkat cells Grakoui et al., 1999). The central region, known as the central (Nath et al., 2016) but its function was not explored. Girdin (also supramolecular activation cluster (cSMAC), is characterized by the known as GIV, G α-interacting vesicle-associated protein) exhibits a accumulation of T cell receptors (TCR) and protein kinase C-theta variety of signaling functions and is involved in cytoskeletal (PKC-θ) (Monks et al., 1998). Surrounding the cSMAC is an outer reorganization and integrin signaling (Leyme et al., 2016, 2015; zone known as the peripheral supramolecular activation cluster Aznar et al., 2016; Weng et al., 2010). (pSMAC), which is characterized by clusters of the lymphocyte We initially showed there are two DISC1 isoforms expressed in function-associated protein 1 (LFA-1, also known as integrin Jurkat cells, the full-length L isoform (DISC1L) and the Lv splice variant (DISC1Lv) (Nakata et al., 2009). We show that the L isoform accumulates at the immunological synapse, whereas DISC1Lv is 1Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA. associated with mitochondria. When DISC1 was deleted using 2Cellink LLC, 100 Franklin St., Boston, MA 02110, USA. 3Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson CRISPR/Cas9, actin accumulation at the immunological synapse was University, Philadelphia, PA 19107, USA. greatly reduced and members of the dynein complex (dynein, NDE1 and LIS1), which colocalizes with ADAP (FYN-binding protein 1) at *Author for correspondence ([email protected]) the pSMAC, remain clustered together near the center of the synapse N.M., 0000-0001-7690-5234; S.N., 0000-0001-5778-7615; A.R., 0000-0002- (Combs et al., 2006; Nath et al., 2016). We also found that DISC1 2922-5778; N.A., 0000-0003-1494-6270; Y.S., 0000-0002-9685-0223; M.P., 0000- forms a complex with Girdin and that deletion of Girdin gave a 0003-2524-4039 phenotype similar to that of DISC1 knockout (DISC1-KO) cells. Handling Editor: Daniel Billadeau When DISC1L or Girdin were reintroduced as cDNAs into their Received 14 December 2019; Accepted 26 May 2020 respective deletion mutant cell lines, the DISC1–dynein complex was Journal of Cell Science 1 RESEARCH ARTICLE Journal of Cell Science (2020) 133, jcs242875. doi:10.1242/jcs.242875 again localized at the pSMAC and actin accumulation at the synapse expression was only partially reduced and that cells quickly was restored to levels seen in wild-type (WT) Jurkat cells. recovered. As an alternative, a CRISPR/Cas9 construct targeted to The loss of actin accumulation and failure of the dynein complex DISC1 was used to disrupt the gene. Chemical selection and cell to locate at the pSMAC suggested that there was a connection sorting were then used to obtain a pure DISC1 deletion cell line between actin assembly and localization of the NDE1–dynein (DISC1-KO). Absence of DISC1 expression in this cell line was complex. To explore this further, we treated Jurkat cells with verified by immunoblotting and an absence of DISC1 cytochalasin B (CytB) or latrunculin B (LatB) to disrupt actin immunofluorescence at the synapse (Fig. S2). polymerization prior to formation of conjugates with staphylococcal One of the most obvious effects of DISC1 deletion was the loss of enterotoxin E (SEE)-coated Raji cells. These treatments resulted in actin accumulation at the immunological synapse, as detected by loss of the dynein complex from the synapse and a failure of staining with phalloidin-TRITC (Fig. 2A,B). Actin accumulation microtubule organizing center (MTOC) translocation to the was analyzed by plotting average phalloidin-TRITC fluorescence immunological synapse. Moreover, we showed that after Jurkat for pixels within segments spanning the width of the synapse; 30 cells are activated by anti-TCR Ig, DISC1 co-immunoprecipitates wild-type (WT) and 30 DISC1-KO cells were analyzed (Fig. 2C). with talin. Because talin binds to LFA-1, this finding may explain For the five segments closest to the immunological synapse there how the dynein complex becomes associated with the pSMAC was significant difference in phalloidin-TRITC fluorescence (Klapholz and Brown, 2017). (P<0.001). Additionally, to determine whether disruption of DISC1 had an effect on LFA-1 recruitment to the synapse, we RESULTS immunostained for the LFA-1 adapter talin in WT and DISC1-KO DISC1 isoform L promotes actin polymerization at the cells (Fig. 2A,B). The results show that talin was recruited to the immunological synapse immunological synapse in the absence of DISC1. Initial immunostaining studies showed that DISC was concentrated To verify that the loss of actin at the immunological synapse was around the MTOC in unstimulated Jurkat cells but accumulated at specific to deletion of DISC1, we introduced DISC1-eGFP the synapse after conjugation with SEE-coated Raji cells (Fig. 1A). constructs for L and Lv isoforms into DISC1-KO cells. However, These results were not unique to Jurkat cells as DISC1 also neither of the DISC1-eGFP isoforms restored actin accumulation at accumulates at the immunological synapse in NK-92-Daudi cell the synapse (Fig. S3). We then repeated the experiment using pairs and in mouse OT-1 CTLs engaged with peptide-pulsed EL4 DISC1 constructs without the fused eGFP. In this case, only cells (Fig. S1). expression of the L isoform was able to restore visible actin staining We then proceeded to clone DISC1 from a Jurkat cDNA library. at the immunological synapse (Fig. 2D,E). Finally, to determine Sequencing of the clones revealed two previously identified whether detectable actin remained at the immunological synapse in isoforms, L and Lv (Nakata et al., 2009). We used these two the DISC1-KO cell line, we used confocal microscopy together clones to produce DISC1-eGFP chimeras, which were expressed in with phalloidin-TRITC staining to compare WT Jurkat cells Jurkat cells. We found that DISC1 isoform Lv localized to and DISC1-KO cells that were either untreated or treated with organelles that accumulate near the synapse after stimulation with LatB to disrupt actin (Fig.
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