Abnormalities in chemokine receptor recycling in chronic lymphocytic leukemia

Abstract

In addition to their modulation through de novo expression and degradation, surface levels of chemokine receptors are tuned by their ligand-dependent recycling to the plasma membrane, which ensures that engaged receptors become rapidly available for further rounds of signaling. Dysregulation of this process contributes to the pathogenesis of chronic lymphocytic leukemia (CLL) by enhancing surface expression of chemokine receptors, thereby favoring leukemic cell accumulation in the protective niche of lymphoid organs. In this review, we summarize our current understanding of the process of chemokine receptor recycling, focusing on the impact of its dysregulation in CLL.

Keywords: CLL; Chemokine receptor; Desensitization; Recycling; Resensitization.

Fig. 1

Main steps of chemokine receptor recycling. (1) Receptor phosphorylation. Binding to the cognate chemokine ligand triggers phosphorylation of the chemokine receptor (CR) by phosphorylating kinases (PK). Associated G proteins are then activated by conformational change and elicit signaling pathways to chemotaxis and survival. (2) β-arrestin binding. β-arrestin, recruited to phosphorylated receptor, inhibits the interaction of G proteins with the receptor, thereby blocking signaling and leading to the short-term desensitization of the receptor. (3) Receptor internalization. β-arrestin, by recruiting clathrin and AP2, mediates internalization of the chemokine receptor through clathrin-coated pits and their localization in Rab5⁺ early endosomes (EE) leading to the long-term desensitization of the receptor. (4) Receptor dephosphorylation and recycling. Phosphoserine/threonine phosphatases (PP) dephosphorylate the receptor which releases β-arrestin, proceeds along the Rab11⁺ endosomal pathway, and is eventually recycled to the cell surface

Fig. 2

An imbalance in the surface levels of homing and egress receptors promotes CLL cell accumulation in the prosurvival lymphoid niche. a Homing of B lymphocytes to lymphoid organs is controlled by surface expression of the homing receptors CCR7, CXCR4, and CXCR5 whose ligands are secreted in the stroma. B-cell exit is guided by the egress receptor S1PR1, whose ligand S1P is highly concentrated in body fluids. b CLL B cells express higher surface levels of homing receptors and lower levels of S1PR1. The resulting prolonged residency in the stroma of lymphoid organs promotes leukemic cell survival and contributes to CLL pathogenesis

Fig. 3

CXCR4 and CCR7 recycling is enhanced in CLL B cells. a Ligand binding to the chemokine receptor (CR) triggers receptor phosphorylation, recruitment of β-arrestin, and receptor internalization in the Rab5⁺ endocytic compartment. Here, the phosphoserine phosphatase PP2B, activated by Ca²⁺ mobilized in response to chemokine receptor triggering, dephosphorylates internalized chemokine receptors, which then release β-arrestin and enter the recycling route in association with Rab11⁺ endosomes. p66Shc, a negative regulator of chemokine receptor-dependent signaling, restrains Ca²⁺ mobilization, thereby lowering PP2B activity and chemokine receptor entry into the recycling route. b In CLL B cells, defective p66Shc expression leads to enhanced chemokine receptor-dependent Ca²⁺ mobilization, which results in increased PP2B activity and chemokine receptor dephosphorylation and recycling