Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane.
Mol Cell
; 81(7): 1397-1410.e9, 2021 04 01.
Article
in En
| MEDLINE
| ID: mdl-33725486
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phospholipids
/
Cell Membrane
/
Caspases
/
DNA-Binding Proteins
/
Apoptosis Regulatory Proteins
/
Proteolysis
/
Membrane Proteins
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2021
Type:
Article
Affiliation country:
Taiwan