scholarly journals Rab7b regulates dendritic cell migration by linking lysosomes to the actomyosin cytoskeleton

2021 ◽  
Author(s):  
Katharina Vestre ◽  
Irene Persiconi ◽  
Marita Borg Distefano ◽  
Nadia Mensali ◽  
Noemi Antonella Guadagno ◽  
...  
Keyword(s):  
Cell Migration ◽  
Immune Cell ◽  
Myosin Ii ◽  
Small Gtpase ◽  
Peripheral Tissues ◽  
3 Dimensional ◽  
Late Endosomes ◽  
Dendritic Cell Migration ◽  
Transcription Factor Eb ◽  
Actomyosin Cytoskeleton

Lysosomal signaling facilitates the migration of immune cells by releasing calcium to activate the actin-based motor myosin II at the cell rear. However, how the actomyosin cytoskeleton physically associates to lysosomes is unknown. We have previously identified myosin II as a direct interactor of Rab7b, a small GTPase that mediates the transport from late endosomes/lysosomes to the TGN. Here, we show that Rab7b regulates the migration of dendritic cells (DCs) in 1- and 3-dimensional environments. DCs are immune sentinels that transport antigens from peripheral tissues to lymph nodes to activate T lymphocytes and initiate adaptive immune responses. We found that lack of Rab7b reduces myosin II light chain phosphorylation and the activation of the transcription factor EB (TFEB), which controls lysosomal signaling and is required for fast DC migration. Furthermore, we demonstrate that Rab7b interacts with the lysosomal calcium channel TRPML1, enabling the local activation of myosin II at the cell rear. Altogether, our findings identify Rab7b as the missing physical link between lysosomes and the actomyosin cytoskeleton, allowing control of immune cell migration through lysosomal signaling.

The human cytokine TSLP triggers a cell-autonomous dendritic cell migration in confined environments

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3862-3869 ◽  
Author(s):  
Maria-Isabel Fernandez ◽  
Mélina L. Heuzé ◽  
Carolina Martinez-Cingolani ◽  
Elisabetta Volpe ◽  
Marie-Helene Donnadieu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Myosin Ii ◽  
Unexpected Finding ◽  
Critical Function ◽  
Peripheral Tissues ◽  
3 Dimensional ◽  
Actin Cortex ◽  
Dendritic Cell Migration ◽  
A Cell ◽  
Confined Environment

Abstract Dendritic cells (DCs) need to migrate in the interstitial environment of peripheral tissues to reach secondary lymphoid organs and initiate a suitable immune response. Whether and how inflamed tissues instruct DCs to emigrate is not fully understood. In this study, we report the unexpected finding that the epithelial-derived cytokine TSLP triggers chemokinesis of resting primary human DCs in a cell-autonomous manner. TSLP induced the polarization of both microtubule and actin cytoskeletons and promoted DC 3-dimensional migration in transwell as well as in microfabricated channels that mimic the confined environment of peripheral tissues. TSLP-induced migration relied on the actin-based motor myosin II and was inhibited by blebbistatin. Accordingly, TSLP triggered the redistribution of phosphorylated myosin II regulatory light chain to the actin cortex, indicating that TSLP induces DC migration by promoting actomyosin contractility. Thus, TSLP produced by epithelial cells in inflamed tissue has a critical function in licensing DCs for cell-autonomous migration. This indicates that cytokines can directly trigger cell migration, which has important implications in immune physiopathology and vaccine design.

scholarly journals Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5703-5710 ◽  
Author(s):  
Tim Lämmermann ◽  
Jörg Renkawitz ◽  
Xunwei Wu ◽  
Karin Hirsch ◽  
Cord Brakebusch ◽  
...  
Keyword(s):  
Specific Interaction ◽  
Leading Edge ◽  
Small Gtpase ◽  
3 Dimensional ◽  
Dendritic Cell Migration ◽  
Adhesive Interactions ◽  
Actomyosin Contraction ◽  
Extracellular Environment ◽  
Pericellular Proteolysis

Abstract Mature dendritic cells (DCs) moving from the skin to the lymph node are a prototypic example of rapidly migrating amoeboid leukocytes. Interstitial DC migration is directionally guided by chemokines, but independent of specific adhesive interactions with the tissue as well as pericellular proteolysis. Instead, the protrusive flow of the actin cytoskeleton directly drives a basal mode of locomotion that is occasionally supported by actomyosin contractions at the trailing edge to propel the cell's rigid nucleus. We here delete the small GTPase Cdc42 in DCs and find that actin flow and actomyosin contraction are still initiated in response to chemotactic cues. Accordingly, the cells are able to polarize and form protrusions. However, in the absence of Cdc42 the protrusions are temporally and spatially dysregulated, which leads to impaired leading edge coordination. Although this defect still allows the cells to move on 2-dimensional surfaces, their in vivo motility is completely abrogated. We show that this difference is entirely caused by the geometric complexity of the environment, as multiple competing protrusions lead to instantaneous entanglement within 3-dimensional extracellular matrix scaffolds. This demonstrates that the decisive factor for migrating DCs is not specific interaction with the extracellular environment, but adequate coordination of cytoskeletal flow.

Abstract A80: The effects of CCL3 on dendritic cell migration and immune cell activation

2020 ◽  
Author(s):  
Teilo H. Schaller ◽  
Kristen A. Batich ◽  
Kelly Hotchkiss ◽  
Xiuyu Cui ◽  
Luis Sanchez-Perez ◽  
...  
Keyword(s):  
Cell Migration ◽  
Dendritic Cell ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Cell Activation ◽  
Dendritic Cell Migration

scholarly journals Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Jaimy Jose ◽  
Monira Hoque ◽  
Johanna Engel ◽  
Syed S. Beevi ◽  
Mohamed Wahba ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Mutant Cell ◽  
Chinese Hamster ◽  
Focal Adhesions ◽  
Migration And Invasion ◽  
3 Dimensional ◽  
Late Endosomes ◽  
Niemann Pick ◽  
Mutant Cells

AbstractCholesterol is considered indispensable for cell motility, but how physiological cholesterol pools enable cells to move forward remains to be clarified. The majority of cells obtain cholesterol from the uptake of Low-Density lipoproteins (LDL) and here we demonstrate that LDL stimulates A431 squamous epithelial carcinoma and Chinese hamster ovary (CHO) cell migration and invasion. LDL also potentiated epidermal growth factor (EGF) -stimulated A431 cell migration as well as A431 invasion in 3-dimensional environments, using organotypic assays. Blocking cholesterol export from late endosomes (LE), using Niemann Pick Type C1 (NPC1) mutant cells, pharmacological NPC1 inhibition or overexpression of the annexin A6 (AnxA6) scaffold protein, compromised LDL-inducible migration and invasion. Nevertheless, NPC1 mutant cells established focal adhesions (FA) that contain activated focal adhesion kinase (pY397FAK, pY861FAK), vinculin and paxillin. Compared to controls, NPC1 mutants display increased FA numbers throughout the cell body, but lack LDL-inducible FA formation at cell edges. Strikingly, AnxA6 depletion in NPC1 mutant cells, which restores late endosomal cholesterol export in these cells, increases their cell motility and association of the cholesterol biosensor D4H with active FAK at cell edges, indicating that AnxA6-regulated transport routes contribute to cholesterol delivery to FA structures, thereby improving NPC1 mutant cell migratory behaviour.

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