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Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization
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The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis
Yang Li1, Shachi P Vyas1, Isha Mehta2
1Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
The Journal of Experimental Medicine
|July 26, 2024
Summary
Arid5a protein regulates kidney inflammation in autoantibody-mediated glomerulonephritis (AGN) by controlling protein synthesis. Blocking Arid5a prevents kidney damage by impacting IL-17 signaling pathways.
Area of Science:
- Immunology
- Molecular Biology
- Nephrology
Background:
- Autoantibody-mediated glomerulonephritis (AGN) involves kidney inflammation requiring new treatments.
- Interleukin-17 (IL-17) contributes to AGN pathology through renal tubular epithelial cells (RTECs).
- Downstream IL-17 signaling in kidney disease remains incompletely understood.
Purpose of the Study:
- To investigate the role of the RNA binding protein Arid5a in IL-17-driven kidney pathology.
- To elucidate the molecular mechanisms by which Arid5a influences AGN.
Main Methods:
- Utilized Arid5a knockout (Arid5a-/-) mice to assess AGN development.
- Employed transcriptome-wide RIP-Seq to identify Arid5a RNA targets.
- Analyzed protein synthesis and IL-17 signaling pathways.
Main Results:
- Arid5a was upregulated in human and mouse AGN.
- Arid5a-/- mice showed resistance to AGN, with reduced inflammation and cytokine expression.
- Arid5a directly binds IL-17 target mRNAs, including those for C/EBPβ and C/EBPδ.
- Arid5a regulates protein synthesis and C/EBP levels post-transcriptionally.
- IL-17 induces Arid5a nuclear export and association with 18S rRNA, impacting translation.
Conclusions:
- Arid5a is a critical mediator of IL-17-driven kidney inflammation in AGN.
- Arid5a functions by regulating ribosome interactions and global protein synthesis.
- Targeting Arid5a may offer a therapeutic strategy for AGN.
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