Coronin-1A Links Cytoskeleton Dynamics to TCRαβ-Induced Cell Signaling

Abstract

Actin polymerization plays a critical role in activated T lymphocytes both in regulating T cell receptor (TCR)-induced immunological synapse (IS) formation and signaling. Using gene targeting, we demonstrate that the hematopoietic specific, actin- and Arp2/3 complex-binding protein coronin-1A contributes to both processes. Coronin-1A-deficient mice specifically showed alterations in terminal development and the survival of αβT cells, together with defects in cell activation and cytokine production following TCR triggering. The mutant T cells further displayed excessive accumulation yet reduced dynamics of F-actin and the WASP-Arp2/3 machinery at the IS, correlating with extended cell-cell contact. Cell signaling was also affected with the basal activation of the stress kinases sAPK/JNK1/2; and deficits in TCR-induced Ca2+ influx and phosphorylation and degradation of the inhibitor of NF-κB (IκB). Coronin-1A therefore links cytoskeleton plasticity with the functioning of discrete TCR signaling components. This function may be required to adjust TCR responses to selecting ligands accounting in part for the homeostasis defect that impacts αβT cells in coronin-1A deficient mice, with the exclusion of other lympho/hematopoietic lineages.

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

“…Concurrent with this hypothesis, we observed a significant decrease in the lysosomal enzyme hexosaminidase B that plays a role in degradation of internalized Staphylococcus (106). Taken together, the regulatory systems described generate precise control of actin filament and network formation and participate in multiple aspects of pathogenesis (107)(108)(109)(110)(111)(112).…”

GRAIL (Gene Related to Anergy in Lymphocytes) Regulates Cytoskeletal Reorganization through Ubiquitination and Degradation of Arp2/3 Subunit 5 and Coronin 1A

“…An earlier study of coronin 1A knock-out mice reported that coronin 1A has an Arp2/3-5-dependent inhibitory effect on F-actin formation and concluded that coronin 1A is indispensable for TCR signaling (27,29). In the present study, overexpression of coronin 1A restored the proliferative response.…”

“…Although ubiquitination of target proteins was almost completely lost when either K63R or K48R mutant ubiquitin was used, it remains unclear whether Arp2/3-5 and coronin 1A are ubiquitinated via Lys-48, Lys-63, or both sites. To address this issue, characterization of ubiquitin chain using MALDI-TOF-MS or mutants in which Lys-48 or Lys-63 is the only lysine residue that can mediate the ubiquitin chain formation will be needed for future studies The immunological synapse is important in sustained signaling and delivery of a subset of effector cytokines by CD4 ϩ T cells (25,29,31,32). Although the precise contribution of actin cytoskeletal remodeling to T cell signaling and biologic function is not completely understood, both anergic T cells and T cells overexpressing GRAIL have been reported to form unstable immunologic synapses (4,38).…”

“…Coronin 1A has been shown to bind the Arp2/3 complex and inhibit F-actin nucleation by freezing the Arp2/3 complex in its inactive conformation (28). Coronin 1A-deficient T cells exhibit reduced cytokine production, including of IL-2 and IFN-␥, and altered F-actin reorganization (29). Moreover, a nonsense mutation in coronin 1A was identified as a gene alteration associated with the Lmb3 locus, which plays a major role in modulating autoimmunity in Fas lpr mice (30).…”

Experimental assessment of the contribution of electrodynamic interactions to long-distance recruitment of biomolecular partners: Theoretical basis

“…Indeed, protein-protein and protein-nucleic acid interactions in vivo generally take place within complex structural scaffolds such as the membrane cytoskeleton or the chromatin envelope, which are themselves the subject of highly dynamical regulations (e.g., Refs. [40,41]); and may also possibly interfere with the spatiotemporal control of the given reactions (e.g., Refs. [42,43]).…”