An interaction between Scribble and the NADPH oxidase complex controls M1 macrophage polarization and function.
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.
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.
Weiyue
W
Zheng
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.
Masataka
M
Umitsu
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.|Cancer Research Institute, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ishaan
I
Jagan
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada.
Charles W
http://orcid.org/0000-0001-5818-818X
CW
Tran
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.
Noboru
N
Ishiyama
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.
Michael
M
BeGora
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.
Kiyomi
K
Araki
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada.
Pamela S
PS
Ohashi
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.
Mitsuhiko
M
Ikura
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.|Cancer Research Institute, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02115, USA.
Senthil K
SK
Muthuswamy
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C480591:SCRIB protein, human; C508433:scrib protein, mouse
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