MERTK coordinates efferocytosis by regulating integrin localization and activation

Efferocytosis is mediated by MERTK in many tissues, but the signaling pathway and molecular mechanisms used by MERTK to engulf apoptotic cells is largely unknown. Here, using mass spectrometry and super-resolution microscopy, we identified 180 nm receptor complexes comprised of MERTK, β2 integrins and several associated signaling molecules. Efferocytosis was found to be dependent on both MERTK and β2 integrins, with MERTK inducing the conformational change of β2 integrins from low to high-affinity via a PI3K-dependent pathway, with the active integrins then mediating the expansion of an efferocytic synapse around the apoptotic cell. This synapse was highly structured, with MERTK retained by ligand-induced clustering in the synapse centre, while β2 integrins and actin form a Src family kinase and FAK-dependent expanding ring that defined the leading edge of the efferocytic synapse. These findings provide new insights into the function of this crucial homeostatic receptor and provide new insights into how MERTK mutations and signaling defects might contribute to inflammatory and autoimmune diseases.