Cross-Regulation of F-Box Protein FBXL2 with T-bet and TNF-α during Acute and Chronic Lung Allograft Rejection
Year: 2022
Type: article
Abstract: Chronic lung allograft dysfunction is the major barrier to long-term survival in lung transplant recipients. Evidence supports type 1 alloimmunity as the predominant response in acute/chronic lung rejection, but the immunoregulatory mechanisms remain incompletely understood. We studied the combinatorial F-box E3 ligase system: F-box protein 3 (FBXO3; proinflammatory) and F-box and leucine-rich repeat protein 2 (FBXL2; anti-inflammatory and regulates TNFR-associated factor [TRAF] protein). Using the mouse orthotopic lung transplant model, we evaluated allografts from BALB/c → C57BL/6 (acute rejection; day 10) and found significant induction of FBXO3 and diminished FBXL2 protein along with elevated T-bet, IFN-γ, and TRAF proteins 1-5 compared with isografts. In the acute model, treatment with costimulation blockade (MR1/CTLA4-Ig) resulted in attenuated FBXO3, preserved FBXL2, and substantially reduced T-bet, IFN-γ, and TRAFs 1-5, consistent with a key role for type 1 alloimmunity. Immunohistochemistry revealed significant changes in the FBXO3/FBXL2 balance in airway epithelia and infiltrating mononuclear cells during rejection compared with isografts or costimulation blockade-treated allografts. In the chronic lung rejection model, DBA/2J/C57BL/6F1 > DBA/2J (day 28), we observed persistently elevated FBXO3/FBXL2 balance and T-bet/IFN-γ protein and similar findings from lung transplant recipient lungs with chronic lung allograft dysfunction versus controls. We hypothesized that FBXL2 regulated T-bet and found FBXL2 was sufficient to polyubiquitinate T-bet and coimmunoprecipitated with T-bet on pulldown experiments and vice versa in Jurkat cells. Transfection with FBXL2 diminished T-bet protein in a dose-dependent manner in mouse lung epithelial cells. In testing type 1 cytokines, TNF-α was found to negatively regulate FBXL2 protein and mRNA levels. Together, our findings show the combinatorial E3 ligase FBXO3/FBXL2 system plays a role in the regulation of T-bet through FBXL2, with negative cross-regulation of TNF-α on FBXL2 during lung allograft rejection.
Source: The Journal of Immunology
Authors: Antu Das, Xingan Wang, Jianxin Wei, Aki Hoji, Tiffany A Coon, Iulia Popescu, Mark Brown, Sheila Frizzell, Carlo J Iasella, Kentaro Noda, John C Sembrat, Kaitlyn Devonshire, Stefanie J Hannan, Mark E Snyder, Joseph M Pilewski, Pablo G Sanchez, Divay Chandra, Rama K Mallampalli, Jonathan K Alder, Bill B Chen, John F McDyer
Institutions: University of Pittsburgh, The Ohio State University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Regulation of the interferon lamda receptor by influenza, G2431470425, Role of F-Box Proteins in Lung Transplantation, G5884491534, Systematic Investigation of Protein Ubiquitination in ARDS, Immunosuppression in Acute Lung Injury, Role of FBXO24 mediated ubiquitination of FoxP1 protein in the pathogenesis and treatment of COPD, E3 Ligase-Mediated Immunosuppression in Acute Lung Injury, G977340541
OpenAlex ID: W4296161897