Actin-Bundling Protein L-Plastin Regulates T Cell Activation

Wang, Chen; Morley, Sharon Celeste; Donermeyer, David L.; Peng, Ivan; Lee, Wyne P.; DeVoss, Jason; Danilenko, Dimitry M.; Lin, Zhonghua; Zhang, Juan; Zhou, Jie; Allen, Paul M.; Brown, Eric J.

doi:10.4049/jimmunol.1001424

Cited by 63 publications

(67 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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).…”

Section: Discussionsupporting

confidence: 48%

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

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

A thorough understanding of the molecular details of the interactions between bacteria and host are critical to ultimately prevent disease. Recent technological advances allow simultaneous analysis of host and bacterial protein and metabolic profiles from a single small tissue sample to provide insight into pathogenesis. We used the chinchilla model of human otitis media to determine, for the first time, the most expansive delineation of global changes in protein and metabolite profiles during an experimentally induced disease. After 48 h of infection with nontypeable Haemophilus influenzae, middle ear tissue lysates were analyzed by high-resolution quantitative two-dimensional liquid chromatography-tandem mass spectrometry. Dynamic changes in 105 chinchilla proteins and 66 metabolites define the early proteomic and metabolomic signature of otitis media. Our studies indicate that establishment of disease coincides with actin morphogenesis, suppression of inflammatory mediators, and bacterial aerobic respiration. We validated the observed increase in the actin-remodeling complex, Arp2/3, and experimentally showed a role for Arp2/3 in nontypeable Haemophilus influenzae invasion. Direct inhibition of actin branch morphology altered bacterial invasion into host epithelial cells, and is supportive of our efforts to use the information gathered to modify outcomes of disease. The twenty-eight nontypeable Haemophilus influenzae proteins identified participate in carbohydrate and amino acid metabolism, redox homeostasis, and include cell wall-associated metabolic proteins. Quantitative characterization of the molecular signatures of infection will redefine our understanding of host response driven developmental changes during pathogenesis. These data represent the first comprehensive study of host protein and metabolite profiles in vivo in response to infection and show the feasibility of extensive characterization of host protein profiles during disease. Identification of novel protein targets and metabolic biomarkers will advance development of therapeutic and diagnostic options for treatment of disease. Molecular & Cellular Proteomics 15: 10.1074/mcp.M115.052498, 1117-1138, 2016.Our current understanding of the global changes that occur during infection is primarily based upon transcriptional profiles of either the host or the bacteria. However, a significant component of disease progression is dependent upon posttranscriptional processes. Recent advances in the application of two-dimensional tandem mass spectrometry have dramatically increased sensitivity to allow simultaneous analyses of multiple molecules from very small biological samples. In this study, we report the comprehensive proteomic and metabolomic profiling of middle ear tissues using samples that are smaller than those typically obtained from a human biopsy. Proteomic and metabolomic analyses of samples as small as biopsies will revolutionize the elucidation of the mechanisms From the

show abstract

Section: Discussionsupporting

confidence: 48%

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

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…3D) also points to a role for this bundling protein in stabilizing/maintaining F-actin levels. Recent studies using T lymphocytes isolated from L-plastin knockout mice and depletion of L-plastin protein in human T lymphocytes with siRNAs have also implicated this bundling protein in immune synapse formation (46,47), with loss of Lplastin impairing Ag-induced F-actin levels (46) or TCR-induced lamellipodia formation (47). Collectively, these results imply that L-plastin is a crucial regulator of both chemokine-induced polarization and immune synapse formation.…”

Section: Discussionmentioning

confidence: 66%

L-Plastin Regulates Polarization and Migration in Chemokine-Stimulated Human T Lymphocytes

Freeley

O’Dowd

Paul

et al. 2012

The Journal of Immunology

105

View full text Add to dashboard Cite

Chemokines such as SDF-1α play a crucial role in orchestrating T lymphocyte polarity and migration via polymerization and reorganization of the F-actin cytoskeleton, but the role of actin-associated proteins in this process is not well characterized. In this study, we have investigated a role for L-plastin, a leukocyte-specific F-actin–bundling protein, in SDF-1α–stimulated human T lymphocyte polarization and migration. We found that L-plastin colocalized with F-actin at the leading edge of SDF-1α–stimulated T lymphocytes and was also phosphorylated at Ser5, a site that when phosphorylated regulates the ability of L-plastin to bundle F-actin. L-plastin phosphorylation was sensitive to pharmacological inhibitors of protein kinase C (PKC), and several PKC isoforms colocalized with L-plastin at the leading edge of SDF-1α–stimulated lymphocytes. However, PKC ζ, an established regulator of cell polarity, was the only isoform that regulated L-plastin phosphorylation. Knockdown of L-plastin expression with small interfering RNAs demonstrated that this protein regulated the localization of F-actin at the leading edge of chemokine-stimulated cells and was also required for polarization, lamellipodia formation, and chemotaxis. Knockdown of L-plastin expression also impaired the Rac1 activation cycle and Akt phosphorylation in response to SDF-1α stimulation. Furthermore, L-plastin also regulated SDF-1α–mediated lymphocyte migration on the integrin ligand ICAM-1 by influencing velocity and persistence, but in a manner that was independent of LFA-1 integrin activation or adhesion. This study, therefore, demonstrates an important role for L-plastin and the signaling pathways that regulate its phosphorylation in response to chemokines and adds L-plastin to a growing list of proteins implicated in T lymphocyte polarity and migration.

show abstract

“…It is known that GBP-1 binds (besides homodimerization and heterodimerization with GBP family members) (41,42) to the cytoskeletal proteins b-IIITubulin and PIM1 (14). Five among the 10 potential GBP-1 binding partners identified by us by mass spectrometry (multisynthetase complex auxiliary component p43, plastin-2, STOML2, MRCL3, and bIIspectrin) are described to be involved in the remodeling of the (actin-) cytoskeleton (33,36,43,44) and 4 of these 5 (plastin-2, STOML2, MRCL3, and bII-spectrin) to influence T cell activation (30,(32)(33)(34)(35)(36)(44)(45)(46). Based on the fact that IL-2 expression is abrogated in plastin-2 knockout mice, we suspected plastin-2 to be involved in the GBP-1-mediated IL-2 regulation.…”

Section: Discussionmentioning

confidence: 99%

Guanylate Binding Protein 1–Mediated Interaction of T Cell Antigen Receptor Signaling with the Cytoskeleton

Förster

Paster

Supper

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

GTPases act as important switches in many signaling events in cells. Although small and heterotrimeric G proteins are subjects of intensive studies, little is known about the large IFN-inducible GTPases. In this article, we show that the IFN-γ–inducible guanylate binding protein 1 (GBP-1) is a regulator of T cell activation. Silencing of GBP-1 leads to enhanced activation of early T cell Ag receptor/CD3 signaling molecules, including Lck, that is translated to higher IL-2 production. Mass spectrometry analyses showed that regulatory cytoskeletal proteins, like plastin-2 that bundles actin fibers and spectrin β-chain, brain 1 that links the plasma membrane to the actin cytoskeleton, are binding partners of GBP-1. The spectrin cytoskeleton influences cell spreading and surface expression of TCR/CD3 and the leukocyte phosphatase CD45. We found higher cell spreading and enhanced surface expression of TCR/CD3 and CD45 in GBP-1 silenced T cells that explain their enhanced TCR/CD3 signaling. We conclude that GBP-1 is a downstream processor of IFN-γ via which T cells regulate cytoskeleton-dependent cell functions.

show abstract

Actin-Bundling Protein L-Plastin Regulates T Cell Activation

Cited by 63 publications

References 44 publications

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

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

L-Plastin Regulates Polarization and Migration in Chemokine-Stimulated Human T Lymphocytes

Guanylate Binding Protein 1–Mediated Interaction of T Cell Antigen Receptor Signaling with the Cytoskeleton

Contact Info

Product

Resources

About