The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity
Citations Over TimeTop 13% of 2016 papers
Abstract
Identification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis. Hrd1 facilitates T-cell proliferation by the destruction of cyclin-dependent kinase inhibitor p27(kip1), and deletion of p27(kip1) in Hrd1-null T-cells rescues proliferative capacity but not the production of cytokines, including IL-2, IFN-γ and IL-17. T-cell expression of Hrd1 is higher in patients with multiple sclerosis than in healthy individuals, and knockdown of Hrd1 in human CD4(+) T cells inhibits activation and differentiation to Th1 and Th17 cells. Our study identifies Hrd1 as a previously unappreciated positive regulator of T cells and implies that Hrd1 is a potential therapeutic target for autoimmune diseases.
Related Papers
- → Ubiquitin and a charged loop regulate the ubiquitin E3 ligase activity of Ark2C(2022)32 cited
- → The E3 ubiquitin ligases regulate inflammation in cardiovascular diseases(2023)26 cited
- → Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics(2021)5 cited
- → Analysis of ubiquitin E3 ligase activity using selective polyubiquitin binding proteins(2012)20 cited
- Functional analysis of the ubiquitin ligase Hrd1p with the ubiquitin -conjugating enzyme Ubc7p(2007)