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Lymphoma

Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL

Leukemia volume 34, pages 553–566 (2020)Cite this article

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Abstract

Regulating B-cell receptor (BCR) signaling after antigenic stimulation is essential to properly control immune responses. Currently known mechanisms of inhibiting BCR signaling are via co-receptor stimulation and downstream immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation. Herein we demonstrate that BCR stimulation induces rapid and reversible palmitoylation of the SCF-FBXO10 ubiquitin E3 ligase. This results in FBXO10 relocation to the cell membrane, where it targets the human germinal center-associated lymphoma (HGAL) protein for ubiquitylation and degradation, leading to decreases in both BCR-induced calcium influx and phosphorylation of proximal BCR effectors. Importantly, FBXO10 recognition and degradation of HGAL is phosphorylation independent and instead relies on a single evolutionarily conserved HGAL amino acid residue (H91) and FBXO10 relocalization to the cytoplasmic membrane. Together our findings demonstrate the first evidence of negative BCR signaling regulation from direct BCR stimulation and define the temporospatial functions of the FBXO10-HGAL axis. FBXO10 is infrequently mutated in DLBCL but some of these mutations deregulate BCR signaling. These observations may have important implications on lymphomagenesis and other immune processes.

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Acknowledgements

XJ is supported by Stanley J. Glaser Foundation Research Award (UM SJG 2017–8), American Cancer Society Institutional Research Grant (#98–277–13), and the University of Miami Sylvester Comprehensive Cancer Center. VTM was supported by BioNIUM Pilot Project Award. ISL is supported by the American Society of Hematology Bridge grant, the Dwoskin, Recio and Anthony Rizzo Families Foundations, Jaime Erin Follicular Lymphoma Research Consortium, and the University of Miami Sylvester Comprehensive Cancer Center. We thank University of Miami flow cytometry core facility for cell sorting and calcium analysis.

Author contributions

FG: designed and performed experiments, analyzed data, and wrote the manuscript. YL: performed experiments. XJ: performed experiments. XL: performed experiments. DR: provided reagents, designed experiments, and analyzed data. CL: analyzed data and wrote the manuscript. KK: performed experiments. MM: performed analysis of mutational databases. LR: provided valuable reagents. RV: analyzed data and performed experiments. FV: analyzed data. VTM: performed experiments and analyzed data. ISL: conceptualized these studies, analyzed data, and wrote the manuscript. All the authors read this manuscript and approved its content.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Fengjie Guo, Yuan Luo, Xiaoyu Jiang, XiaoQing Lu, Chen Lossos, Marco Magistri, Ramiro Verdun & Izidore S. Lossos

  2. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA

    Fengjie Guo, Yuan Luo, Xiaoyu Jiang, XiaoQing Lu, Marco Magistri & Izidore S. Lossos

  3. Department of Pathology, Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA

    Domenico Roberti

  4. Department of Pathology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Kranthi Kunkalla & Francisco Vega

  5. Department of Medicine and Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Lixin Rui

  6. Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA

    Vincent T. Moy

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  1. Fengjie Guo
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Correspondence to Izidore S. Lossos.

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Guo, F., Luo, Y., Jiang, X. et al. Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL. Leukemia 34, 553–566 (2020). https://doi.org/10.1038/s41375-019-0579-5

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