ArhGAP12 plays dual roles in Stabilin-2 mediated efferocytosis: Regulates Rac1 basal activity and spatiotemporally turns off the Rac1 to orchestrate phagosome maturation
| Autor: | Je-Yoel Cho, Seung Yoon Park, Jae Hoon Pyo, Soyoun Kim, In San Kim, Jae Do Yoo, Sang Yeob Kim, Dong Jun Bae, Junyoung Seo, Wonhwa Cho |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Phosphatidylinositol 4
5-Diphosphate rac1 GTP-Binding Protein Phagocytic cup GTPase-activating protein Cell Adhesion Molecules Neuronal Phagocytosis Down-Regulation RAC1 CDC42 Cell Line Mice Phagosomes Phagosome maturation Animals Humans Efferocytosis Molecular Biology Adaptor Proteins Signal Transducing Phagosome Phagocytes Chemistry GTPase-Activating Proteins Cell Biology Actins Cell biology Gene Knockdown Techniques Lysosomes |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1866:1595-1607 |
| ISSN: | 0167-4889 |
| DOI: | 10.1016/j.bbamcr.2019.07.003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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