ArhGAP12 plays dual roles in Stabilin-2 mediated efferocytosis: Regulates Rac1 basal activity and spatiotemporally turns off the Rac1 to orchestrate phagosome maturation
- Authors
- Bae, Dong-Jun; Seo, Junyoung; Kim, Sang-Yeob; Park, Seung-Yoon; Yoo, Jae Do; Pyo, Jae-Hoon; Cho, Wonhwa; Cho, Je-Yoel; Kim, Soyoun; Kim, In-San
- Issue Date
- 2019-10
- Publisher
- ELSEVIER
- Citation
- BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v.1866, no.10, pp.1595 - 1607
- 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.
- Keywords
- CELL CORPSE CLEARANCE; ACTIN CYTOSKELETON; APOPTOTIC CELLS; PHAGOCYTOSIS; PROTEIN; CDC42; PHOSPHATIDYLSERINE; ACTIVATION; ENGULFMENT; RECEPTOR; CELL CORPSE CLEARANCE; ACTIN CYTOSKELETON; APOPTOTIC CELLS; PHAGOCYTOSIS; PROTEIN; CDC42; PHOSPHATIDYLSERINE; ACTIVATION; ENGULFMENT; RECEPTOR; ArhGAP12; Rac1 activity; Efferocytosis; Phosphatidylinositol-4,5-bisphosphate; Phagosome maturation
- ISSN
- 0167-4889
- URI
- https://pubs.kist.re.kr/handle/201004/119497
- DOI
- 10.1016/j.bbamcr.2019.07.003
- Appears in Collections:
- KIST Article > 2019
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