Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
JCI Insight. 2019 Mar 7;4(5). doi: 10.1172/jci.insight.121887.
Treg differentiation, maintenance, and function are controlled by the transcription factor FoxP3, which can be destabilized under inflammatory or other pathological conditions. Tregs can be destabilized under inflammatory or other pathological conditions, but the underlying mechanisms are not fully defined. Herein, we show that inflammatory cytokines induce ER stress response, which destabilizes Tregs by suppressing FoxP3 expression, suggesting a critical role of the ER stress response in maintaining Treg stability. Indeed, genetic deletion of Hrd1, an E3 ligase critical in suppressing the ER stress response, leads to elevated expression of ER stress-responsive genes in Treg and largely diminishes Treg suppressive functions under inflammatory condition. Mice with Treg-specific ablation of Hrd1 displayed massive multiorgan lymphocyte infiltration, body weight loss, and the development of severe small intestine inflammation with aging. At the molecular level, the deletion of Hrd1 led to the activation of both the ER stress sensor IRE1α and its downstream MAPK p38. Pharmacological suppression of IRE1α kinase, but not its endoribonuclease activity, diminished the elevated p38 activation and fully rescued the stability of Hrd1-null Tregs. Taken together, our studies reveal ER stress response as a previously unappreciated mechanism underlying Treg instability and that Hrd1 is crucial for maintaining Treg stability and functions through suppressing the IRE1α-mediated ER stress response.
Treg 的分化、维持和功能受转录因子 FoxP3 的控制，FoxP3 在炎症或其他病理条件下可能会失稳。Treg 在炎症或其他病理条件下可能会失稳，但潜在机制尚未完全确定。在此，我们表明炎性细胞因子诱导 ER 应激反应，通过抑制 FoxP3 表达来破坏 Treg，提示 ER 应激反应在维持 Treg 稳定性方面起着关键作用。事实上，Hrd1 的基因缺失，一种在抑制 ER 应激反应中至关重要的 E3 连接酶，导致 Treg 中 ER 应激反应相关基因的表达升高，并在炎症条件下大大降低 Treg 的抑制功能。在 Treg 特异性缺失 Hrd1 的小鼠中，表现为多器官淋巴细胞浸润、体重减轻以及随着年龄增长出现严重的小肠炎症。在分子水平上，Hrd1 的缺失导致 ER 应激传感器 IRE1α及其下游 MAPK p38 的激活。IRE1α 激酶的药理学抑制，但不是其内切核酸酶活性，可减弱升高的 p38 激活，并完全挽救 Hrd1 缺失 Treg 的稳定性。总之，我们的研究揭示了 ER 应激反应是 Treg 不稳定的一种以前未被认识的机制，而 Hrd1 通过抑制 IRE1α 介导的 ER 应激反应对维持 Treg 的稳定性和功能至关重要。
