Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 43; pp. 1 - 12
• Main Authors: Xu, Xuehua, Wen, Xi, Moosa, Amer, Bhimani, Smit, Jin, Tian
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26-10-2021
• Subjects: Actin; Actins - immunology; Adaptation; AKT protein; Biological Sciences; Cell migration; Cell Movement; Cell Polarity; Chemotactic factors; Chemotaxis; Chemotaxis, Leukocyte - immunology; Cofilin; Concentration gradient; G protein-coupled receptors; Gene Knockdown Techniques; HL-60 Cells; Humans; Leukocytes (neutrophilic); N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophil Activation - drug effects; Neutrophil Activation - genetics; Neutrophil Activation - immunology; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - physiology; Phosphorylation; ras GTPase-Activating Proteins - deficiency; ras GTPase-Activating Proteins - genetics; ras GTPase-Activating Proteins - immunology; ras Proteins - antagonists & inhibitors; ras Proteins - immunology; Receptors, G-Protein-Coupled - immunology; Sensitivity enhancement; Shelterin Complex - immunology; Signal Transduction; Telomere-Binding Proteins - immunology; adaptation; small GTPase Ras; CAPRI; GAP; chemotaxis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2002162118

Neutrophils sense and migrate through an enormous range of chemoattractant gradients through adaptation. Here, we reveal that in human neutrophils, calcium-promoted Ras inactivator (CAPRI) locally controls the GPCR-stimulated Ras adaptation. Human neutrophils lacking CAPRI (caprikd
) exhibit chemoattractant-induced, nonadaptive Ras activation; significantly increased phosphorylation of AKT, GSK-3α/3β, and cofilin; and excessive actin polymerization. caprikd
cells display defective chemotaxis in response to high-concentration gradients but exhibit improved chemotaxis in low- or subsensitive-concentration gradients of various chemoattractants, as a result of their enhanced sensitivity. Taken together, our data reveal that CAPRI controls GPCR activation-mediated Ras adaptation and lowers the sensitivity of human neutrophils so that they are able to chemotax through a higher-concentration range of chemoattractant gradients.