An interaction between Scribble and the NADPH oxidase complex controls M1 macrophage polarization and function
Abstract
The polarity protein Scribble (SCRIB) regulates apical-basal polarity, directional migration and tumour suppression in Drosophila and mammals. Here we report that SCRIB is an important regulator of myeloid cell functions including bacterial infection and inflammation. SCRIB interacts directly with the NADPH oxidase (NOX) complex in a PSD95/Dlg/ZO-1 (PDZ)-domain-dependent manner and is required for NOX-induced reactive oxygen species (ROS) generation in culture and in vivo. On bacterial infection, SCRIB localized to phagosomes in a leucine-rich repeat-dependent manner and promoted ROS production within phagosomes to kill bacteria. Unexpectedly, SCRIB loss promoted M1 macrophage polarization and inflammation. Thus, SCRIB uncouples ROS-dependent bacterial killing activity from M1 polarization and inflammatory functions of macrophages. Modulating the SCRIB-NOX pathway can therefore identify ways to manage infection and inflammation with implications for chronic inflammatory diseases, sepsis and cancer.
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Nitric oxide synthase adaptor protein and NADPH oxidase bind directly to the fourth Scribble PDZ domain, a domain not required for binding either β-PIX or GUKh.
“Nitric oxide synthase adaptor protein and NADPH oxidase, on the other hand, bind directly to the fourth Scribble PDZ domain (Richier et al., 2010; Zheng et al., 2016), a domain not required for binding either β-PIX or GUKh.”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Zheng et al., 2016
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References 39 · Cited by 60
- Authors
- Zheng, W., Umitsu, M., Jagan, I., Tran, C. W., Ishiyama, N., BeGora, M., Araki, K., Ohashi, P. S., Ikura, M., & Muthuswamy, S. K.
- Affiliations
- University of Toronto (CA)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Muthuswamy, Senthil K.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2016-10-03
- Volume
- 18
- Issue
- 11
- Pages
- 1244-1252
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2528883448
- Cited by
- 60
- References
- 39
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 18 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 6
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- Scribble, NADPH oxidase, M1 macrophage polarization, reactive oxygen species, phagosome, bacterial killing, inflammation, PDZ domain, myeloid cells, infection, apical-basal polarity
- MeSH terms
- Animals, Cell Membrane, Humans, Inflammation, Macrophages, Membrane Proteins, Phagosomes, Cell Polarity, Reactive Oxygen Species, NADPH Oxidases, Myeloid Cells, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Mice
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