Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

Schulz, Anna; Stutte, Susanne; Hogl, Sebastian; Luckashenak, Nancy; Dudziak, Diana; Leroy, Céline; Forné, Ignasi; Imhof, Axel; Müller, Stephan; Brakebusch, Cord; Lichtenthaler, Stefan F.; Brocker, Thomas

doi:10.1083/jcb.201503128

Cited by 27 publications

(25 citation statements)

References 87 publications

(106 reference statements)

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“…7Fb). As reported previously (37,38), Cdc42 silencing by transfection with siCdc42 also decreased the formation of F-actin stress fibers in IECs, similar to what was observed in HuR-silenced cells (data not shown). In sum, these results strongly suggest that control of Cdc42 translation by HuR critically regulates cell migration by modulating the subcellular reorganization of cytoskeleton F-actin after wounding.…”

Section: Resultssupporting

confidence: 73%

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

Liu

Zhuang

Xiao

et al. 2017

Molecular and Cellular Biology

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The mammalian intestinal mucosa exhibits a spectrum of responses after acute injury and repairs itself rapidly to restore the epithelial integrity. The RNAbinding protein HuR regulates the stability and translation of target mRNAs and is involved in many aspects of gut epithelium homeostasis, but its exact role in the regulation of mucosal repair after injury remains unknown. We show here that HuR is essential for early intestinal epithelial restitution by increasing the expression of cell division control protein 42 (Cdc42) at the posttranscriptional level. HuR bound to the Cdc42 mRNA via its 3= untranslated region, and this association specifically enhanced Cdc42 translation without an effect on the Cdc42 mRNA level. Intestinal epithelium-specific HuR knockout not only decreased Cdc42 levels in mucosal tissues, but it also inhibited repair of damaged mucosa induced by mesenteric ischemia/reperfusion in the small intestine and by dextran sulfate sodium in the colon. Furthermore, Cdc42 silencing prevented HuR-mediated stimulation of cell migration over the wounded area by altering the subcellular distribution of F-actin. These results indicate that HuR promotes early intestinal mucosal repair after injury by increasing Cdc42 translation and demonstrate the importance of HuR deficiency in the pathogenesis of delayed mucosal healing in certain pathological conditions.

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Section: Resultssupporting

confidence: 73%

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

Liu

Zhuang

Xiao

et al. 2017

Molecular and Cellular Biology

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“…Th2 lipid antigens disturb the polarization of the MTOC and IL4 by reducing the Cdc42 protein level in iNKT cells DGK and Cdc42 have been previously shown to regulate MTOC polarization in several cell types. [34][35][36] In our studies, an inhibitor of DGK, DGK II, only inhibited the reorientation of the MTOC toward the IS if it was added before iNKT cells were activated by αGCpulsed RBL.CD1d cells ( Supplementary Fig. S5A, B).…”

Section: Resultsmentioning

confidence: 72%

Spatial distribution of IL4 controls iNKT cell-DC crosstalk in tumors

et al. 2019

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The spatiotemporal distribution of cytokines orchestrates immune responses in vivo, yet the underlying mechanisms remain to be explored. We showed here that the spatial distribution of interleukin-4 (IL4) in invariant natural killer T (iNKT) cells regulated crosstalk between iNKT cells and dendritic cells (DCs) and controlled iNKT cell-mediated T-helper type 1 (Th1) responses. The persistent polarization of IL4 induced by strong lipid antigens, that is, α-galactosylceramide (αGC), caused IL4 accumulation at the immunological synapse (IS), which promoted the activation of the IL4R-STAT6 (signal transducer and activator of transcription 6) pathway and production of IL12 in DCs, which enhanced interferon-γ (IFNγ) production in iNKT cells. Conversely, the nonpolarized secretion of IL4 induced by Th2 lipid antigens with a short or unsaturated chain was incapable of enhancing this iNKT cell-DC crosstalk and thus shifted the immune response to a Th2-type response. The nonpolarized secretion of IL4 in response to Th2 lipid antigens was caused by the degradation of Cdc42 in iNKT cells. Moreover, reduced Cdc42 expression was observed in tumorinfiltrating iNKT cells, which impaired IL4 polarization and disturbed iNKT cell-DC crosstalk in tumors.

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“…Whether Ii recruits Myosin II by controlling Cdc42 and/or Arp2/3 activity remains to be addressed. Interestingly, it was recently shown that Cdc42‐deficient DCs not only exhibit impaired macropinocytosis but also further accumulate Ii and Myosin II at the cell periphery suggesting that the three proteins are functionally linked . Anyhow, these results indicate that DCs adapt their migratory behavior to their functional requirements: environment sampling and Ag capture for immature DCs and fast migration to lymph nodes for T‐cell activation for mature DCs.…”

Section: The Membrane–cytoskeleton Interface Allows the Spatio‐tempormentioning

confidence: 89%

Dynamics of the membrane–cytoskeleton interface in MHC class II‐restricted antigen presentation

Bretou

Kumari

Malbec

et al. 2016

Immunological Reviews

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Antigen presentation refers to the ability of cells to show MHC-associated determinants to T lymphocytes, leading to their activation. MHC class II molecules mainly present peptide-derived antigens that are internalized by endocytosis in antigen-presenting cells (APCs). Here, we describe how the interface between cellular membranes and the cytoskeleton regulates the various steps that lead to the presentation of exogenous antigens on MHC class II molecules in the two main types of APCs: dendritic cells (DCs) and B lymphocytes. This includes antigen uptake, processing, APC migration, and APC-T cell interactions. We further discuss how the interaction between APC-specific molecules and cytoskeleton elements allows the coordination of antigen presentation and cell migration in time and space.

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Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

Abstract: Cdc42 control of actin dynamics keeps DCs in an immature state, and loss of Cdc42 activity facilitates secretion and rapid up-regulation of intracellular molecules to the cell surface, which shows that Cdc42 contributes to DC immunogenicity by regulating the DC actin cytoskeleton.

Cited by 27 publications

References 87 publications

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

Spatial distribution of IL4 controls iNKT cell-DC crosstalk in tumors

Dynamics of the membrane–cytoskeleton interface in MHC class II‐restricted antigen presentation

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