2. Academic Validation
  3. A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis

A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis

  • Nat Commun. 2022 Dec 24;13(1):7929. doi: 10.1038/s41467-022-35604-8.
Jianting Shi # 1,  Xun Wu # 1,  Ziyi Wang 1,  Fang Li 1,  Yujiao Meng 1 2,  Rebecca M Moore 1,  Jian Cui 1,  Chenyi Xue 1,  Katherine R Croce 3,  Arif Yurdagul Jr 4,  John G Doench 5,  Wei Li 6 7,  Konstantinos S Zarbalis 8 9 10,  Ira Tabas 3 11 12,  Ai Yamamoto 3 13,  Hanrui Zhang 14
Affiliations

Affiliations

  • 1 Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 2 Beijing University of Chinese Medicine, Beijing, China.
  • 3 Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
  • 4 Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 6 Center for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.
  • 7 Department of Genomics and Precision Medicine, George Washington University, Washington, DC, USA.
  • 8 University of California at Davis, Department of Pathology and Laboratory Medicine, Sacramento, CA, 95817, USA.
  • 9 Shriners Hospitals for Children Northern California, Sacramento, CA, 95817, USA.
  • 10 UC Davis MIND Institute, Sacramento, CA, 95817, USA.
  • 11 Department of Medicine, Columbia University, New York, NY, USA.
  • 12 Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
  • 13 Department of Neurology, Columbia University, New York, NY, USA.
  • 14 Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. hz2418@cumc.columbia.edu.
  • # Contributed equally.
PMID: 36566259 DOI: 10.1038/s41467-022-35604-8
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z