The retromer complex promotes apoptotic cell degradation during efferocytosis
Efficient clearance of dead cells, termed efferocytosis, is essential for maintaining tissue homeostasis. Although the cellular and molecular mechanisms regulating apoptotic cell (AC) internalization are well established, our understanding of AC digestion upon engulfment remains elusive. Here, we show that the retromer subunits are recruited to AC-containing phagosomes during efferocytosis and promote AC corpse degradation. Mechanistically, retromer stabilizes NOX2, a key regulator for LC3 recruitment to AC-containing phagosomes, leading to the maturation of phagolysosomes and corpse degradation. Meanwhile, TBC1D5, a binding partner for both retromer and LC3, also accelerates phagolysosomal maturation and AC degradation. Hence, our study indicates that retromer promotes LC3 recruitment and phagolysosomal maturation through stabilizing NOX2 and interacting with TBC1D5. This work elucidates a novel role of retromer in AC degradation and suggests a new avenue to explore the potential of retromer-stabilizing strategies to restore efficient AC clearance in disease. Overall design: Mouse BMDMs treated with siVps35 and incubated with apoptotic cells (AC)