The role of DISC1 in the organization of the T-cell immunological synapse

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dc.contributor.advisorPoenie, Martin F.
dc.contributor.committeeMemberDe Lozanne, Arturo
dc.contributor.committeeMemberChan, Clarence S
dc.contributor.committeeMemberJiang, Ning
dc.contributor.committeeMemberTucker, Haley O
dc.contributor.committeeMemberEhrlich, Lauren I
dc.creatorMaskalenko, Nicholas Alexander
dc.creator.orcid0000-0001-7690-5234
dc.date.accessioned2021-10-11T23:46:27Z
dc.date.available2021-10-11T23:46:27Z
dc.date.created2019-08
dc.date.issued2019-09-24
dc.date.submittedAugust 2019
dc.date.updated2021-10-11T23:46:29Z
dc.description.abstractWhen T-cells contact an antigenic target or antigen-presenting cell, signaling through the T-cell receptor triggers formation of a specialized junction known as the immunological synapse (IS). In a previous study, DISC1 (Disrupted in Schizophrenia 1) was identified as a component of the IS in T-cells, where it forms a complex with dynein, Nde1, and Lis1. Here we show that there are two isoforms of DISC1 expressed in T-cells, one (DISC1 Lv) that colocalizes with mitochondria and the other (DISC1 L) that accumulates at the IS. The accumulation of DISC1 at the IS is also observed in OT-1 CTLs and NK cells. Additionally, we show that disrupting DISC1 using CRISPR/Cas9 technology leads to many changes at the synapse. Each isoform upon reintroduction restores specific changes. The translocation of mitochondria was dependent on the Lv isoform. Loss of the L isoform results in a defect in MTOC translocation, failure of Nde1 to move from the center of the IS to the pSMAC, and greatly reduced actin accumulation at the IS. This last effect depends on the association of DISC1 with Girdin, such that loss of expression of either protein gives the same phenotype. Girdin is involved in cytoskeletal remodeling in other cells but its function in T cells has not been previously described. The results of this work contribute to the understanding of MTOC translocation and mitochondrial movements, but they also generate new questions about the role and regulation of actin at the synapse. The loss of actin in Girdin or DISC1 deletions does not have a severe effect on MTOC translocation as is seen in cells treated with actin inhibitors. However, these treatments lead to a complete loss of Nde1, Lis1, and dynein from the synapse, suggesting that the dynein complex is ultimately linked to actin. These results point to DISC1 and Girdin functioning in a novel actin signaling pathway working at the IS
dc.description.departmentCellular and Molecular Biology
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/2152/88682
dc.identifier.urihttp://dx.doi.org/10.26153/tsw/15616
dc.language.isoen
dc.subjectDISC1
dc.subjectDynein
dc.subjectGirdin
dc.subjectImmunological synapse
dc.subjectT cell
dc.titleThe role of DISC1 in the organization of the T-cell immunological synapse
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentCellular and Molecular Biology
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorThe University of Texas at Austin
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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