UBXN3B is crucial for B lymphopoiesisResearch in context
Tingting Geng,
Duomeng Yang,
Tao Lin,
Andrew G. Harrison,
Binsheng Wang,
Ziming Cao,
Blake Torrance,
Zhichao Fan,
Kepeng Wang,
Yanlin Wang,
Long Yang,
Laura Haynes,
Gong Cheng,
Anthony T. Vella,
Richard A. Flavell,
Joao P. Pereira,
Erol Fikrig,
Penghua Wang
Affiliations
Tingting Geng
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Duomeng Yang
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Tao Lin
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Andrew G. Harrison
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Binsheng Wang
Center on Aging and Department of Genetics and Genome Sciences, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Ziming Cao
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Blake Torrance
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Zhichao Fan
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Kepeng Wang
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Yanlin Wang
Department of Medicine, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Long Yang
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
Laura Haynes
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Gong Cheng
Department of Basic Sciences, School of Medicine, Tsinghua University, Beijing, China
Anthony T. Vella
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA
Richard A. Flavell
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06510, USA
Joao P. Pereira
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06510, USA
Erol Fikrig
Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06510, USA
Penghua Wang
Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA; Corresponding author. Department of Immunology, School of Medicine, University of Connecticut, UConn Health, Farmington, CT, 06030, USA.
Summary: Background: The ubiquitin regulatory X (UBX) domain-containing proteins (UBXNs) are putative adaptors for ubiquitin ligases and valosin-containing protein; however, their in vivo physiological functions remain poorly characterised. We recently showed that UBXN3B is essential for activating innate immunity to DNA viruses and controlling DNA/RNA virus infection. Herein, we investigate its role in adaptive immunity. Methods: We evaluated the antibody responses to multiple viruses and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza in tamoxifen-inducible global and constitutive B cell-specific Ubxn3b knockout mice; quantified various immune populations, B lineage progenitors/precursors, B cell receptor (BCR) signalling and apoptosis by flow cytometry, immunoblotting and immunofluorescence microscopy. We also performed bone marrow transfer, single-cell and bulk RNA sequencing. Findings: Both global and B cell-specific Ubxn3b knockout mice present a marked reduction in small precursor B-II (>60%), immature (>70%) and mature B (>95%) cell numbers. Transfer of wildtype bone marrow to irradiated global Ubxn3b knockouts restores normal B lymphopoiesis, while reverse transplantation does not. The mature B population shrinks rapidly with apoptosis and higher pro and activated caspase-3 protein levels were observed following induction of Ubxn3b knockout. Mechanistically, Ubxn3b deficiency leads to impaired pre-BCR signalling and cell cycle arrest. Ubxn3b knockout mice are highly vulnerable to respiratory viruses, with increased viral loads and prolonged immunopathology in the lung, and reduced production of virus-specific IgM/IgG. Interpretation: UBXN3B is essential for B lymphopoiesis by maintaining constitutive pre-BCR signalling and cell survival in a cell-intrinsic manner. Funding: United States National Institutes of Health grants, R01AI132526 and R21AI155820.
