Other
18 Authors
- Harrison AG,
- Fikrig E,
- Pereira JP,
- Fan Z,
- Wang P,
- Yang D,
- Wang Y,
- Geng T,
- Flavell RA,
- Yang L,
- Torrance B,
- Lin T,
- Wang B,
- Cheng G,
- Wang K,
- Haynes L,
- Vella AT,
- Cao Z
| First Author | Geng T | Year | 2024 |
| Journal | EBioMedicine | Volume | 106 |
| Pages | 105248 | PubMed ID | 39018756 |
| Mgi Jnum | J:354634 | Mgi Id | MGI:7706509 |
| Doi | 10.1016/j.ebiom.2024.105248 | Citation | Geng T, et al. (2024) UBXN3B is crucial for B lymphopoiesis. EBioMedicine 106:105248 |
| abstractText | 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. |
