Abstract
ABSTRACTLysosomal signaling facilitates the migration of immune cells by releasing Ca2+ 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 trans-Golgi network (TGN). Here, we show that Rab7b regulates the migration of dendritic cells (DCs) in one- and three-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 the 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 Ca2+ channel TRPML1 (also known as MCOLN1), enabling the local activation of myosin II at the cell rear. Taken together, our findings identify Rab7b as the missing physical link between lysosomes and the actomyosin cytoskeleton, allowing control of immune cell migration through lysosomal signaling. This article has an associated First Person interview with the first author of the paper.
Highlights
Dendritic cells (DCs) are professional antigen-presenting cells that engulf extracellular material in peripheral tissues and transport it to lymph nodes for presentation to T cells
We previously reported that the small GTPase Rab7b, which regulates the transport from late endosomes towards the trans-Golgi network (TGN) (Borg Distefano et al, 2018; Progida et al, 2010, 2012), interacts directly with the actin motor protein myosin II (Borg et al, 2014; Distefano et al, 2015)
As we did not detect any significant differences in the size or number of podosomes per cell in cells depleted of Rab7b compared to control cells (Fig. 1C,D), we conclude that Rab7b does not affect podosome formation, but rather their distribution and the polarization of mature human DCs
Summary
Dendritic cells (DCs) are professional antigen-presenting cells that engulf extracellular material in peripheral tissues and transport it to lymph nodes for presentation to T cells. While immature DCs are characterized by a high antigen uptake capacity and a slow intermittent migration mode (Chabaud et al, 2015), mature DCs are less capable of antigen uptake but are highly motile (Vargas et al, 2016). This increase in their migration capacity, together with the upregulation of the CCR7 chemokine receptor at their surface, promotes their migration to lymph nodes for the initiation of adaptive immune responses (Mellman and Steinman, 2001). DCs strongly rely on their ability to migrate to exert their immunosurveillance function (Alvarez et al, 2008)
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