[초청강연] Molecular tension authenticates apoptotic cells being phagocytosed

Phagocytosis of apoptotic cells, called efferocytosis, is an essential cellular process by coordinated
signaling between ‘eat-me’ and ‘don’t eat-me’ signals. The unique feature of efferocytosis is that it
is accompanied by massive cytoskeleton and plasma membrane dynamics to ingest apoptotic cells
as large as phagocytes. However, whether the dynamics generate a signal and, if any, how it
modulates signaling during efferocytosis remains elusive. Here, we report that molecular tension
between phosphatidylserine (PS) and its receptors functions as a checkpoint validating apoptotic
cells being phagocytosed in efferocytosis. Using various approaches including tension-tunable
surrogates of apoptotic cells, we found that tension between PS and PS receptors was generated
through actin polymerization-mediated membrane tension, essential for completion of efferocytosis.
Mechanistically, increased membrane tension via Rac1-dependent actin polymerization at the
phagocytic cup induced the tension leading to PI3K activation, which results in Rac1 inactivation
and myosin II phosphorylation required for phagocytic cup closure. Our observations imply that
tension between PS and PS receptor is a mechanical signal that serves as a checkpoint to
determine whether apoptotic cells should be fully phagocytosed or not. Furthermore, the findings
provide insights how chemical and mechanical signaling are elaborated for the integrity of
efferocytosis.