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<p>LC3-associated phagocytosis (LAP) represents a non-canonical function of autophagy proteins in which ATG8-family proteins (LC3 and GABARAP proteins) are lipidated onto single-membrane phagosomes as particles are engulfed by phagocytic cells. LAP plays roles in innate immunity, inflammation and anticancer responses, and is initiated following phagocytosis of particles that stimulate Toll-like receptors (TLR) and Fc receptors as well as following engulfment of dying cells. However, how this molecular process is initiated remains elusive. Here we report that receptors that engage LAP enrich phosphatidylserine (PS) in the phagosome membrane via membrane-proximal domains that are necessary and sufficient for LAP to proceed. Subsequently, PS recruits the Rubicon-containing PI3-kinase complex to initiate the enzymatic cascade leading to LAP. Manipulation of plasma membrane PS content, PS binding by Rubicon or the PS-clustering domains of receptors prevents LAP and delays phagosome maturation. Therefore, the initiation of LAP represents a novel mechanism of PS-mediated signal transduction following ligation of surface receptors.</p>

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Membrane receptors cluster phosphatidylserine to activate LC3-associated phagocytosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月22日

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  • Emilio Boada-Romero,
  • Clifford S. Guy,
  • Gustavo Palacios,
  • Luigi Mari,
  • Suresh Poudel,
  • Zhenrui Li,
  • Piyush Sharma,
  • Douglas R. Green

摘要

LC3-associated phagocytosis (LAP) represents a non-canonical function of autophagy proteins in which ATG8-family proteins (LC3 and GABARAP proteins) are lipidated onto single-membrane phagosomes as particles are engulfed by phagocytic cells. LAP plays roles in innate immunity, inflammation and anticancer responses, and is initiated following phagocytosis of particles that stimulate Toll-like receptors (TLR) and Fc receptors as well as following engulfment of dying cells. However, how this molecular process is initiated remains elusive. Here we report that receptors that engage LAP enrich phosphatidylserine (PS) in the phagosome membrane via membrane-proximal domains that are necessary and sufficient for LAP to proceed. Subsequently, PS recruits the Rubicon-containing PI3-kinase complex to initiate the enzymatic cascade leading to LAP. Manipulation of plasma membrane PS content, PS binding by Rubicon or the PS-clustering domains of receptors prevents LAP and delays phagosome maturation. Therefore, the initiation of LAP represents a novel mechanism of PS-mediated signal transduction following ligation of surface receptors.