Identification of chemo-mechanical signaling downstream of Tim-4 during efferocytosis

Abstract

Efferocytosis, clearance of apoptotic cells, is an essential cellular process accompanying elaborate chemical signaling leading to massive cytoskeletal rearrangement to ingest apoptotic cells. The cytoskeletal dynamics are known to induce tension between phosphatidylserine (PS) and its receptors (PSRs) resulting in PI3K association with Tim-4. However, how Tim-4 recruits PI3K remains elusive. Here, I report that Tim-4 and Axl associate and form a complex with PI3K. I found that PI3K indirectly associated with Tim-4 through Tim-4 mutational analysis, and Axl was a candidate receptor mediating PI3K association with Tim-4. In addition, Axl interacted with Tim-4 and PI3K together, and PI3K association with Tim-4 increased in the presence of Axl. Taken together, these data imply that tension between PS and Tim-4 induce association of Tim-4 with Axl, which lead to PI3K recruitment to the complex and provide insights into how chemical and mechanical signaling are delicately modulated during efferocytosis.