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

TY - JOUR

T1 - Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

AU - Schulz, Anna M

AU - Stutte, Susanne

AU - Hogl, Sebastian

AU - Luckashenak, Nancy

AU - Dudziak, Diana

AU - Leroy, Céline

AU - Forné, Ignasi

AU - Imhof, Axel

AU - Müller, Stephan A

AU - Brakebusch, Cord H

AU - Lichtenthaler, Stefan F

AU - Brocker, Thomas

N1 - © 2015 Schulz et al.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration, and proliferation. To further study the molecular mechanisms of dendritic cell (DC) regulation by Cdc42, we used Cdc42-deficient DCs. Cdc42 deficiency renders DCs phenotypically mature as they up-regulate the co-stimulatory molecule CD86 from intracellular storages to the cell surface. Cdc42 knockout DCs also accumulate high amounts of invariant chain-major histocompatibility complex (MHC) class II complexes at the cell surface, which cannot efficiently present peptide antigens (Ag's) for priming of Ag-specific CD4 T cells. Proteome analyses showed a significant reduction in lysosomal MHC class II-processing proteins, such as cathepsins, which are lost from DCs by enhanced secretion. As these effects on DCs can be mimicked by chemical actin disruption, our results propose that Cdc42 control of actin dynamics keeps DCs in an immature state, and cessation of Cdc42 activity during DC maturation facilitates secretion as well as rapid up-regulation of intracellular molecules to the cell surface.

AB - Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration, and proliferation. To further study the molecular mechanisms of dendritic cell (DC) regulation by Cdc42, we used Cdc42-deficient DCs. Cdc42 deficiency renders DCs phenotypically mature as they up-regulate the co-stimulatory molecule CD86 from intracellular storages to the cell surface. Cdc42 knockout DCs also accumulate high amounts of invariant chain-major histocompatibility complex (MHC) class II complexes at the cell surface, which cannot efficiently present peptide antigens (Ag's) for priming of Ag-specific CD4 T cells. Proteome analyses showed a significant reduction in lysosomal MHC class II-processing proteins, such as cathepsins, which are lost from DCs by enhanced secretion. As these effects on DCs can be mimicked by chemical actin disruption, our results propose that Cdc42 control of actin dynamics keeps DCs in an immature state, and cessation of Cdc42 activity during DC maturation facilitates secretion as well as rapid up-regulation of intracellular molecules to the cell surface.

KW - Actins

KW - Animals

KW - Antigen Presentation

KW - Antigens, CD86

KW - CD4-Positive T-Lymphocytes

KW - Cathepsins

KW - Cell Membrane

KW - Dendritic Cells

KW - F-Box Proteins

KW - Genes, MHC Class II

KW - Lysosomes

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Ubiquitin-Protein Ligases

KW - Up-Regulation

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1083/jcb.201503128

DO - 10.1083/jcb.201503128

M3 - Journal article

C2 - 26553928

SN - 0021-9525

VL - 211

SP - 553

EP - 567

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 3

ER -