SCFFBXW11 Complex Targets Interleukin-17 Receptor A for Ubiquitin-Proteasome-Mediated Degradation

Ben Jin; Sayed Ala Moududee; Dongxia Ge; Pengbo Zhou; Alun R Wang; Yao-Zhong Liu; Zongbing You

doi:10.3390/biomedicines12040755

SCF^FBXW11 Complex Targets Interleukin-17 Receptor A for Ubiquitin-Proteasome-Mediated Degradation

Biomedicines. 2024 Mar 28;12(4):755. doi: 10.3390/biomedicines12040755.

Authors

Ben Jin^{1

2}, Sayed Ala Moududee^{1

2}, Dongxia Ge³, Pengbo Zhou⁴, Alun R Wang⁵, Yao-Zhong Liu⁶, Zongbing You^{1

2

3

7

8

9}

Affiliations

¹ Southeast Louisiana Veterans Health Care System, New Orleans, LA 70112, USA.
² Department of Structural & Cellular Biology, Tulane University, New Orleans, LA 70112, USA.
³ Department of Orthopaedic Surgery, Tulane University, New Orleans, LA 70112, USA.
⁴ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
⁵ Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA 70112, USA.
⁶ Department of Biostatistics and Data Science, Tulane University, New Orleans, LA 70112, USA.
⁷ Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University, New Orleans, LA 70112, USA.
⁸ Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University, New Orleans, LA 70112, USA.
⁹ Tulane Center for Aging, Tulane University, New Orleans, LA 70112, USA.

Abstract

Interleukin-17 (IL-17) is a pro-inflammatory cytokine that participates in innate and adaptive immune responses and plays an important role in host defense, autoimmune diseases, tissue regeneration, metabolic regulation, and tumor progression. Post-translational modifications (PTMs) are crucial for protein function, stability, cellular localization, cellular transduction, and cell death. However, PTMs of IL-17 receptor A (IL-17RA) have not been investigated. Here, we show that human IL-17RA was targeted by F-box and WD repeat domain-containing 11 (FBXW11) for ubiquitination, followed by proteasome-mediated degradation. We used bioinformatics tools and biochemical techniques to determine that FBXW11 ubiquitinated IL-17RA through a lysine 27-linked polyubiquitin chain, targeting IL-17RA for proteasomal degradation. Domain 665-804 of IL-17RA was critical for interaction with FBXW11 and subsequent ubiquitination. Our study demonstrates that FBXW11 regulates IL-17 signaling pathways at the IL-17RA level.

Keywords: FBXW11; IL-17RA; ubiquitin–proteasome-mediated degradation.

Grants and funding

I01 BX004158/BX/BLRD VA/United States