Wiskott-Aldrich Syndrome Protein Regulates Nucleolar Organization and Function in Innate Immune Response

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by the dysfunction of the WAS protein (WASP). Using an isogenic macrophage model derived from genome edited induced pluripotent stem cells we demonstrated that WASP functions in the nucleolus, which plays important roles in immune regulation. The absence of WASP resulted in smaller and misshapen nucleoli, decreased fibrillar center territory, and impaired ribosomal RNA (rRNA) transcription. The nucleolar and rRNA phenotypes were confirmed in WAS patient samples. Furthermore, WASP interacts with nucleolar proteins, including nucleophosmin 1 (NPM1) and fibrillarin (FBL). NPM1 deficiency is known to cause elevated cytokine expression following lipopolysaccharide (LPS) stimulation. Consistently, WASP deficient cells displayed lower levels of NPM1 and a heightened inflammatory cytokine response to LPS, which was rescued by overexpressing NPM1. Together, our research provides novel insights into the critical role of WASP in nucleolar function and the modulation of inflammatory cytokine production.

Zhou, X., Yuan, B., Tian, Y., Zhou, J., Wang, M., shakir, I., Zhang, Y., Bi, C., Aljamal, B. M., Hashem, M. O., Abuyousef, O. I., Abdulwahab, F. M., Ali, A., Dunn, S., Moresco, J., Yates, J. R., Frassoni, F., Gao, X., Alkuraya, F., … Li, M. (2023). Wiskott-Aldrich Syndrome Protein Regulates Nucleolar Organization and Function in Innate Immune Response. https://doi.org/10.1101/2023.08.15.553387

This work was supported by the KAUST Office of Sponsored Research (OSR) under Award No.BAS/1/1080-01 (ML) and URF/1/4716-01. We thank members of Li laboratory for valuable discussion and D. Chen for her administrative support. We thank Ali Reza Behzad of the KAUST Imaging and Characterization Core Lab, Thomas Theussl of the KAUST Visual Computing Center, and staff of Bioscience Core Lab for technical support. We thank Peter Karagiannis from KAUST for suggestions in writing. We also thank Dr. Corrado Calì for suggestions in image processing.

Cold Spring Harbor Laboratory


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