A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 12 2022
24 12 2022
Historique:
received:
19
01
2022
accepted:
13
12
2022
entrez:
24
12
2022
pubmed:
25
12
2022
medline:
28
12
2022
Statut:
epublish
Résumé
Phagocytic clearance of dying cells, termed efferocytosis, is essential for maintaining tissue homeostasis, yet our understanding of efferocytosis regulation remains incomplete. Here we perform a FACS-based, genome-wide CRISPR knockout screen in primary mouse macrophages to search for novel regulators of efferocytosis. The results show that Wdfy3 knockout in macrophages specifically impairs uptake, but not binding, of apoptotic cells due to defective actin disassembly. Additionally, WDFY3 interacts with GABARAP, thus facilitating LC3 lipidation and subsequent lysosomal acidification to permit the degradation of apoptotic cell components. Mechanistically, while the C-terminus of WDFY3 is sufficient to rescue the impaired degradation induced by Wdfy3 knockout, full-length WDFY3 is required to reconstitute the uptake of apoptotic cells. Finally, WDFY3 is also required for efficient efferocytosis in vivo in mice and in vitro in primary human macrophages. This work thus expands our knowledge of the mechanisms of macrophage efferocytosis, as well as supports genome-wide CRISPR screen as a platform for interrogating complex functional phenotypes in primary macrophages.
Identifiants
pubmed: 36566259
doi: 10.1038/s41467-022-35604-8
pii: 10.1038/s41467-022-35604-8
pmc: PMC9789999
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Autophagy-Related Proteins
0
WDFY3 protein, human
0
Wdfy3 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
7929Subventions
Organisme : NHLBI NIH HHS
ID : R00 HL130574
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151611
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS077111
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS127186
Pays : United States
Informations de copyright
© 2022. The Author(s).
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