RRC ID 64297
Author Maruoka M, Zhang P, Mori H, Imanishi E, Packwood DM, Harada H, Kosako H, Suzuki J.
Title Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane.
Journal Mol Cell
Abstract 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.
Volume 81(7)
Pages 1397-1410.e9
Published 2021-4-1
DOI 10.1016/j.molcel.2021.02.025
PII S1097-2765(21)00135-0
PMID 33725486
MeSH Animals Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism* Caspases / genetics Caspases / metabolism* Cell Line, Tumor Cell Membrane / genetics Cell Membrane / metabolism* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* HEK293 Cells Humans Membrane Proteins / genetics Membrane Proteins / metabolism* Mice Phospholipids / genetics Phospholipids / metabolism* Protein Multimerization Proteolysis*
IF 15.584
DNA material pCMV-VSV-G (RDB04392) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)
Human and Animal Cells HCT116(RCB2979)