Journal
MOLECULAR CELL
Volume 81, Issue 7, Pages 1397-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.02.025
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Funding
- AMED-PRIME [15665392]
- AMED-FORCE [19191470]
- MEXT [KAKENHI 15H05651, KAKENHI 16H06456, KAKENHI 20K06486]
- Institute of Advanced Medical Sciences of Tokushima University
- WPI-iCeMS
- Takeda Science Foundation
- Ono Foundation
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This study demonstrates that a nuclear protein fragment, XRCC4, released by caspase-mediated cleavage, directly interacts with the Xkr4 dimer to activate its function on regulating lipid dynamics on the plasma membrane.
Phospholipid scrambling in dying cells promotes phosphatidylserine exposure, a critical process for efferocytosis. We previously identified the Xkr family protein Xkr4 as a phospholipid-scrambling protein, but its activation mechanisms remain unknown. Here we show that Xkr4 is activated in two steps: dimer formation by caspase-mediated cleavage and structural change caused by activating factors. To identify the factors, we developed a new screening system, revival screening, using a CRISPR sgRNA library. Applying this system, we identified the nuclear protein XRCC4 as the single candidate for the Xkr4 activator. Upon apoptotic stimuli, XRCC4, contained in the DNA repair complex, is cleaved by caspases, and its C-terminal fragment with an intrinsically disordered region is released into the cytoplasm. Protein interaction screening showed that the fragment interacts directly with the Xkr4 dimer to activate it. This study demonstrates that caspase-mediated cleavage releases a nuclear protein fragment for direct regulation of lipid dynamics on the plasma membrane.
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