AKAP9 regulates activation-induced retention of T lymphocytes at sites of inflammation

Herter, Jan M.; Grabie, Nir; Culleré, Xavier; Azcutia, Verónica; Rosetti, Florencia; Bennett, Paul M.; Herter-Sprie, Grit S.; Elyaman, Wassim; Luscinskas, Francis W.; Lichtman, Andrew H.; Mayadas, Tanya N.

doi:10.1038/ncomms10182

Cited by 16 publications

(18 citation statements)

References 70 publications

(116 reference statements)

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“…We note that in this study we focused on cells undergoing mesenchymal motility and that other motility types, such as ameboid motility, which are less dependent on MT networks, might not require Golgi MTs. In line with this idea, recent work showed that AKAP450 is not needed for T cell migration into tissues and lymph nodes, although its loss did affect T cell receptor recycling (Herter et al, 2015). Furthermore, a mouse KO study showed that while AKAP450 is essential for spermatogenesis and Sertoli cell maturation, it is not required for mouse viability (Schimenti et al, 2013).…”

Section: Discussionmentioning

confidence: 92%

Molecular Pathway of Microtubule Organization at the Golgi Apparatus

et al. 2016

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The Golgi apparatus controls the formation of non-centrosomal microtubule arrays important for Golgi organization, polarized transport, cell motility, and cell differentiation. Here, we show that CAMSAP2 stabilizes and attaches microtubule minus ends to the Golgi through a complex of AKAP450 and myomegalin. CLASPs stabilize CAMSAP2-decorated microtubules but are not required for their Golgi tethering. AKAP450 is also essential for Golgi microtubule nucleation, and myomegalin and CDK5RAP2 but not CAMSAP2 contribute to this function. In the absence of centrosomes, AKAP450- and CAMSAP2-dependent pathways of microtubule minus-end organization become dominant, and the presence of at least one of them is needed to maintain microtubule density. Strikingly, a compact Golgi can be assembled in the absence of both centrosomal and Golgi microtubules. However, CAMSAP2- and AKAP450-dependent Golgi microtubules facilitate Golgi reorientation and cell invasion in a 3D matrix. We propose that Golgi-anchored microtubules are important for polarized cell movement but not for coalescence of Golgi membranes.

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Section: Discussionmentioning

confidence: 92%

Molecular Pathway of Microtubule Organization at the Golgi Apparatus

et al. 2016

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“…AKAP9 forms a complex with LFA-1 in T lymphocytes undergoing motility, thereby facilitating T cell migration [161]. Recently, Herter et al [162] have demonstrated that AKAP9 is important in effector functions of T cells in a mouse model of glomerulonephritis. They show that effective restimulation of CD4 + by nonprofessional APCs in nonlymphoid tissue is dependent on TCR recycling to the membrane with the help of AKAP9.…”

Section: Effector Pathways-pka and Epac1mentioning

confidence: 99%

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Arumugham

Baldari

2017

Journal of Leukocyte Biology

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T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects. Whereas cAMP compartmentalization has been identified as a central factor in the control of the cAMP-dependent processes in other cell types, this has, as yet, not been addressed in T lymphocytes. In this review, we discuss the role of cAMP in T cell activation and differentiation, with an emphasis on the effects mediated by the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)1, and on the regulatory proteins that may control the generation of local cAMP pools in T cells. We also present an overview of the available tools to image cAMP production at the subcellular level and discuss how bacterial adenylate cyclase (AC) toxins that are known to generate local cAMP pools can be exploited to address the role of cAMP compartmentalization in T cell activation.

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“…2E–G). Prior studies have shown that inflammatory macrophages express less KLF2 than non-classical macrophages (52, 53). From our data, it is possible that many CD11c-expressing Ly-6C lo/mid non-classical monocytes lose KLF2 and upregulate Ly-6C, becoming inflammatory Ly-6C hi monocytes as Itgaxcre-Klf2 fl/fl recipients had increased numbers of CD11c + Ly-6C hi , but not CD11c − Ly-6C hi compared with controls (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses

Alberts-Grill

Engelbertsen

et al. 2016

The Journal of Immunology

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Dendritic cells (DCs), have been implicated as important regulators of innate and adaptive inflammation in many diseases including atherosclerosis. However, the molecular mechanisms by which DCs mitigate or promote inflammatory pathogenesis are only partially understood. Previous studies have shown an important anti-inflammatory role for the transcription factor KLF2 in regulating activation of various cell types that participate in atherosclerotic lesion development, including endothelial cells, macrophages, and T cells. We used a pan-DC, CD11c-specific cre-lox gene knockout mouse model to assess the role of KLF2 in DC activation, function, and control of inflammation in the context of hypercholesterolemia and atherosclerosis. We found that KLF2 deficiency enhanced surface expression of costimulatory molecules CD40 and CD86 in DCs and promoted increased T cell proliferation and apoptosis. Transplant of bone marrow from mice with KLF2-deficient DCs into Ldlr−/− mice aggravated atherosclerosis compared to control mice, most likely due to heightened vascular inflammation evidenced by increased DC presence within lesions, enhanced T cell activation and cytokine production, and increased cell death in atherosclerotic lesions. Together these data indicate that KLF2 governs the degree of DC activation and hence the intensity of pro-atherogenic T cell responses.

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AKAP9 regulates activation-induced retention of T lymphocytes at sites of inflammation

Cited by 16 publications

References 70 publications

Molecular Pathway of Microtubule Organization at the Golgi Apparatus

Molecular Pathway of Microtubule Organization at the Golgi Apparatus

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses

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