Cross Talk between Engulfment Receptors Stabilin-2 and Integrin αvβ5 Orchestrates Engulfment of Phosphatidylserine-Exposed Erythrocytes

Abstract

c Efficient cell corpse clearance is critical for health in organisms. Apoptotic cells displaying phosphatidylserine (PS) are recognized by engulfment receptors and ingested through two conserved pathways. In one pathway, engulfment receptor brain-specific angiogenesis inhibitor 1 (BAI-1) or integrin functions upstream of ELMO/DOCK180 and activate the small GTPase Rac1. In the other pathway, engulfment receptor CED-1 or stabilin-2 acts in concert with the adaptor protein GULP to activate Rac1. Stabilin-2, a PS receptor, facilitates phagocytosis of apoptotic cells and mediates the production of anti-inflammatory cytokines. Here, we propose that the stabilin-2 extracellular domain consisting of integrin-binding fasciclin 1 (FAS1) domains coordinates the activities of the two phagocytic pathways via direct interactions with integrin. Interactions between stabilin-2 and integrin were determined using biochemical assays, including coimmunoprecipitation and fluorescence resonance energy transfer (FRET). These interactions appear to have functional relevance, since knockdown of endogenous ␣v␤5 expression or treatment with a function-blocking ␣v␤5 antibody significantly decreased stabilin-2-mediated phagocytosis in the absence of soluble factors. Our data collectively suggest that the engulfment receptors of the two phagocytic pathways communicate with each other to orchestrate engulfment of damaged erythrocytes. Coordinated phagocytic signaling would be advantageous for physiological and pathological circumstances that require rapid clearance of abnormal (apoptotic or aged) cells.

Hyaluronic Acid Receptor for Endocytosis (HARE)-mediated Endocytosis of Hyaluronan, Heparin, Dermatan Sulfate, and Acetylated Low Density Lipoprotein (AcLDL), but Not Chondroitin Sulfate Types A, C, D, or E, Activates NF-κB-regulated Gene Expression

“…The only ligand that may not be readily apparent as an indicator of tissue function or integrity is ␣M␤2 integrin, which is the major leukocyte integrin expressed on neutrophils. Although the physiological significance is not yet clear, ␣M␤2-HARE interactions mediate leukocyte adhesion to hepatic Secs and clearance of aged erythrocytes by hepatic Secs (41,46,47).…”

Role of NPxY motif in Draper-mediated apoptotic cell clearance in Drosophila

“…In contrast, mammalian stabilin-2, a phosphatidylserinebinding engulfment receptor, uses its NPxY motif to recruit the mammalian orthologue of CED-6 (37). Interestingly, stabilin-2 may also activate the CED-2/ CED-5/CED-12/CED-10 pathway through physical association with α V β 5 (38). Therefore, which of the two conserved signaling pathways is used by NPxY motifcontaining engulfment receptors seemingly depends on the ligand-receptor combination and/or the receptor repertoire in phagocytes.…”

Accelerated receptor shedding inhibits kidney injury molecule-1 (KIM-1)-mediated efferocytosis

“…Phagocytic cells can recognize eat-me signals like PtdSer on apoptotic cells either directly (e.g., KIM-1) (35,44,65) or indirectly via opsonin proteins such as Milk fat globule EGF factor 8 protein (via ␣v␤5-integrin) and growth arrest-specific factor-6 (via Mer), respectively (43,53,77). We speculated that soluble KIM-1 might serve as an opsonin (1,23) to promote phagocytic uptake by tubular epithelial cells within the tubule that do not express KIM-1.…”