Chemotactic G protein-coupled receptors control cell migration by repressing autophagosome biogenesis

Abstract

Chemotactic migration is a fundamental behavior of cells and its regulation is particularly relevant in physiological processes such as organogenesis and angiogenesis, as well as in pathological processes such as tumor metastasis. The majority of chemotactic stimuli activate cell surface receptors that belong to the G protein-coupled receptor (GPCR) superfamily. Although the autophagy machinery has been shown to play a role in cell migration, its mode of regulation by chemotactic GPCRs remains largely unexplored. We found that ligand-induced activation of 2 chemotactic GPCRs, the chemokine receptor CXCR4 and the urotensin 2 receptor UTS2R, triggers a marked reduction in the biogenesis of autophagosomes, in both HEK-293 and U87 glioblastoma cells. Chemotactic GPCRs exert their anti-autophagic effects through the activation of CAPNs, which prevent the formation of pre-autophagosomal vesicles from the plasma membrane. We further demonstrated that CXCR4- or UTS2R-induced inhibition of autophagy favors the formation of adhesion complexes to the extracellular matrix and is required for chemotactic migration. Altogether, our data reveal a new link between GPCR signaling and the autophagy machinery, and may help to envisage therapeutic strategies in pathological processes such as cancer cell invasion.

Colorectal cancer cells respond differentially to autophagy inhibition in vivo

“…Two approaches of autophagy inhibition were compared, namely blocking autophagosome formation versus blocking autophagosome-lysosome fusion, by respectively targeting ATG5 and RAB21 expression through RNA interference, using previously validated siRNA 44,45 . RAB21 was selected given its ability to mediate the sorting of VAMP8 to endolysosomes 44 , the latter being required for autophagosome-lysosome fusion 46 .…”

Endo‐lysosomal sorting of G‐protein‐coupled receptors by ubiquitin: Diverse pathways for G‐protein‐coupled receptor destruction and beyond

“…Finally, GPCRs like the adenosine A2 receptor regulate autophagosome biogenesis in order to inhibit neutrophil apoptosis. Similarly, the urotensin receptor UTS2R and CXCR4 suppress the biogenesis of autophagosomes, a process critical for cell migration. These studies highlight the importance of autophagosomes in the regulation of GPCRs, and the connections between GPCR signaling and the control of autophagosome formation.…”

Evidence for calpains in cancer metastasis

“…Coly et al identified that the novel effects of two chemotactic GPCRs, C‐X‐C motif chemokine receptor (CXCR4) and urotensin 2 receptor, on repressing autophagy rely on CAPN/CAPN activation. The antiautophagic function of CAPN is probably because of the cleavage of several key elements in the formation of pre‐autophagosomal vesicles from the plasma membrane (PM), including the clathrin adaptors phosphatidylinositol binding clathrin assembly protein (PICALM), activator protein‐2 (AP2) complex, and autophagy‐related protein (ATG7; Coly et al, ). In addition, the altered expression of CXCR3, which comprises two splice variants, CXCR3A and CXCR3B, in prostate cancer cells is capable of regulating cell migration and invasion.…”