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. Using mass spectrometry and super-resolution microscopy we have identified 180 nm receptor complexes comprised of MERTK, β2 integrins, and several associated signalling molecules. Efferocytosis is dependent on both MERTK and β2 integrins, with MERTK inducing the conformational change of β2 integrins from low to high-affinity via a PI3-kinase-dependent pathway, with the active integrins then mediating the expansion of an efferocytic synapse around the apoptotic cell. This synapse is 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 which defines the leading edge of the efferocytic synapse. These findings provide new insights into the function of this critical homeostatic receptor and provides new insights into how MERTK mutations and signaling defects may contribute to inflammatory and autoimmune diseases.