CD20 tails interact with the 14-3-3/GEF-H1 complex and microtubule network upon PKCδ phosphorylation

Year: 2026

Type: article

Abstract: CD20 is a four-helix transmembrane protein specifically expressed in B-cells that serves as a prominent target of therapeutic anti-CD20 antibodies. It is localized in a membrane nanocluster harboring the B-cell antigen receptor of IgD class (IgD-BCR), where it functions to maintain the resting state of naïve B-lymphocytes. How CD20 exerts this resting B-cell gatekeeper function is not yet known. Using Ramos and human peripheral blood B-cells, we show here that the serine/threonine kinase PKCδ constitutively phosphorylates serine residues in the two cytosolic tails of CD20. Phosphorylated CD20 becomes a binding target for 14-3-3 adaptor proteins, which link it to the RhoA GDP/GTP exchange factor GEF-H1 and the microtubule network, supporting the function of the IgD-BCR nanocluster. Binding of anti-CD20 antibodies results in microtubule dissociation and replacement of the GEF-H1/CD20 complex with a RhoA-GTP/ROCK1/CD20 complex, which promotes actomyosin contractility. Our study suggests that CD20 not only maintains the resting state of B-lymphocytes by anchoring the microtubule network and controlling the stability of the IgD-BCR nanocluster, but also mediates the microtubule/actin switch in active B-lymphocytes. These findings could have important implications for anti-CD20 antibody treatment and the optimization of therapeutic protocols.

Source: The EMBO Journal

DOI: 10.1038/s44318-026-00781-5

Authors: Kathrin Kläsener, Cindy Eunhee Lee, Julian Bender, Angela Naumann, Lena Reimann, Geoffroy Andrieux, Claudio Mussolino, Nadja Herrmann, Roland Nitschke, Reinhard E Voll, Bettina Warscheid, Klaus Warnatz, Michael Reth

Institutions: University of Freiburg, University Medical Center Freiburg, University of Canberra, University of Würzburg

Language: English

Topic: T-cell and B-cell Immunology

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $7,990

Funders: Roche, Roche Innovation Center Zurich, Deutsche Forschungsgemeinschaft, Albert-Ludwigs-Universität Freiburg, Deutschen Konsortium für Translationale Krebsforschung, National Institutes of Health, Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg, All of Us Research Program

OpenAlex ID: W7154710053