ArhGAP12 plays dual roles in Stabilin-2 mediated efferocytosis: Regulates Rac1 basal activity and spatiotemporally turns off the Rac1 to orchestrate phagosome maturation

Dong Jun Bae, Junyoung Seo, Sang Yeob Kim, Seung Yoon Park, Jae Do Yoo, Jae Hoon Pyo, Wonhwa Cho, Je Yoel Cho, Soyoun Kim, In-San Kim

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The rapid and precise clearance of apoptotic cells (efferocytosis) involves a series of phagocytic processes through which apoptotic cells are recognized, engulfed, and degraded within phagocytes. The Rho-family GTPases critically rearrange the cytoskeleton for these phagocytic processes, but we know little about the mechanisms by which regulatory proteins control the spatiotemporal activities of the Rho-family GTPases. Here, we identify ArhGAP12 as a functional GTPase-activating protein (GAP) of Rac1 during Stabilin-2 mediated efferocytosis. ArhGAP12 constitutively forms a complex with the phosphatidylserine receptor, Stabilin-2, via direct interaction with the downstream protein, GULP, but is released from the complex when Stabilin-2 interacts with apoptotic cells. When the phagocytic cup is closed and the apoptotic cell is surrounded by the phagosomal membrane, ArhGAP12 localizes to the phagocytic cup via a specific interaction with phosphatidylinositol-4,5-bisphosphate, which is transiently biosynthesized in the phagocytic cup. Down-regulation of ArhGAP12 results in sustained Rac1 activity, arrangement of F-actin, and delayed phagosome-lysosome fusion. Our results collectively suggest that ArhGAP12 carries dual roles in Stabilin-2 mediated efferocytosis: it binds to GULP/Stabilin-2 and switches off Rac1 basal activity and switches on the Rac1 by releasing itself from the complex. In addition, the spatiotemporal membrane targeting of ArhGAP12 inactivates Rac1 in a time-specific and spatially coordinated manner to orchestrate phagosome maturation. This may shed light on how other RhoGAPs spatiotemporally inactivate Rac or Cdc42 during phagocytosis by various cells, in different circumstances.

Original languageEnglish
Pages (from-to)1595-1607
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number10
DOIs
Publication statusPublished - 2019 Oct 1

Keywords

  • ArhGAP12
  • Efferocytosis
  • Phagosome maturation
  • Phosphatidylinositol-4,5-bisphosphate
  • Rac1 activity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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