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Nucleolin acts as the receptor for C1QTNF4 and supports C1QTNF4-mediated innate immunity modulation

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article number100513
JournalJournal of Biological Chemistry
Published1 Jan 2021

Bibliographical note

Funding Information: funded by Versus Arthritis PhD studentship 21252 (to S. K. V., D. S. C. G., and T. J. V.). This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (to T. J. V.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We acknowledge financial support through the NIHR-funded BRC Flow Cytometry Core at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Publisher Copyright: © 2021 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


The C1q and TNF related 4 (C1QTNF4) protein is a structurally unique member of the C1QTNF family, a family of secreted proteins that have structural homology with both complement C1q and the tumor necrosis factor superfamily. C1QTNF4 has been linked to the autoimmune disease systemic lupus erythematosus through genetic studies; however, its role in immunity and inflammation remains poorly defined and a cell surface receptor of C1QTNF4 has yet to be identified. Here we report identification of nucleolin as a cell surface receptor of C1QTNF4 using mass spectrometric analysis. Additionally, we present evidence that the interaction between C1QTNF4 and nucleolin is mediated by the second C1q-like domain of C1QTNF4 and the C terminus of nucleolin. We show that monocytes and B cells are target cells of C1QTNF4 and observe extensive binding to dead cells. Imaging flow cytometry experiments in monocytes show that C1QTNF4 becomes actively internalized upon cell binding. Our results suggest that nucleolin may serve as a docking molecule for C1QTNF4 and act in a context-dependent manner through coreceptors. Taken together, these findings further our understanding of C1QTNF4's function in the healthy immune system and how dysfunction may contribute to the development of systemic lupus erythematosus.

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