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  3. A genome-wide base-editing screen uncovers a pivotal role of paxillin δ ubiquitination in influenza virus infection

A genome-wide base-editing screen uncovers a pivotal role of paxillin δ ubiquitination in influenza virus infection

  • Cell Rep. 2025 Jun 24;44(6):115748. doi: 10.1016/j.celrep.2025.115748.
Jiamei Guo 1,  Zhuo Zhou 2,  Ruining Li 1,  Zhifang Xing 1,  Lei Zhang 1,  Shiyi Zhao 3,  Wensheng Wei 4,  Jianwei Wang 5,  Tao Deng 6
Affiliations

Affiliations

  • 1 Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 2 State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. Electronic address: zhouzhuo@gmail.com.
  • 3 State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China.
  • 4 Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
  • 5 State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; NHC Key Laboratory of Systems Biology of Pathogens and ChristopheMe' rieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; Key Laboratory of Respiratory Disease Pathogenomics, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: wangjw28@163.com.
  • 6 Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address: dengt@im.ac.cn.
PMID: 40434888 DOI: 10.1016/j.celrep.2025.115748
Abstract

Dissecting host factors critical for viral Infection and understanding their mechanisms of action is critical for identifying drug targets. Here, we leverage a genome-wide CRISPR base-editing screen to identify functional lysine residues in host factors required for influenza A virus (IAV) replication. Multiple host genes, including GSTM4, FLNC, HMGB1, ZNF236, GRIP1, and PXN, along with regulatory lysine codons, are identified. Among these, paxillin (encoded by PXN) is identified as an important host entry factor. Depletion of paxillin significantly reduces IAV Infection in both cell cultures and mice. Further analysis suggests that the δ isoform of paxillin, rather than the canonical β isoform, plays the key role. Additionally, our data indicate that lysine 68 of paxillin δ undergoes K6-linked ubiquitination and regulates Influenza Virus replication via modulating endosome-dependent viral entry. These observations contribute to understanding how influenza viruses interact with host factors and may inform therapeutic development.

Keywords

CP: Microbiology; CRISPR base-editing screen; influenza A virus; lysine; paxillin δ; ubiquitination.

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