Endoplasmic reticulum (ER)-associated degradation (ERAD) is a mechanism against ER stress, wherein unfolded/misfolded proteins accumulated in the ER are transported to the cytosol for degradation by the ubiquitin-proteasome system. The ER resident E3 ubiquitin ligase HRD1 has been identified as a key ERAD factor that directly catalyzes ubiquitin conjugation onto the unfolded or misfolded proteins for proteasomal degradation. The abnormally increased HRD1 expression was discovered in rheumatoid synovial cells, providing the first evidence for HRD1 dysregulation involved in human inflammatory pathogenesis. Further studies shown that inflammatory cytokines involved in rheumatoid pathogenesis including IL-1β, TNF-α, IL-17 and IL-26 induce HRD1 expression. Recent studies using mice with tissue-specific targeted deletion of HRD1 gene have revealed important functions of HRD1 in immune regulation and inflammatory diseases. HRD1 has been shown critical for dendritic cell expression of antigens to both CD4 and CD8 T cells. Both TCR and costimulatory receptor CD28 signaling induces HRD1 expression, which promotes T cell clonal expansion and IL-2 production. Together with the fact that HRD1 is required for maintaining the stability of regulatory T cell (Treg) stability, HRD1 appears to fine tone T cell immunity. In addition, HRD1 is involved in humoral immune response by regulating early B cell development and maintaining B cell survival upon recognition of specific antigen. HRD1 appears to target its substrates for ubiquitination through, either ERAD-dependent or -independent, at least two distinct molecular mechanisms in a cell or tissue specific manner to achieve its physiological functions. Dysregulation of HRD1 expression and/or it functions are involved in autoimmune inflammatory diseases in particular rheumatoid arthritis and lupus. Here, we review current findings on the mechanism of HRD1 protein in immune regulation and the involvement of HRD1 in the pathogenesis of autoimmune inflammatory diseases.

中文翻译：

---

内质网相关降解及其他：HRD1 在免疫调节和自身免疫中的多任务作用。

内质网 (ER) 相关降解 (ERAD) 是一种对抗 ER 应激的机制，其中积累在 ER 中的未折叠/错误折叠的蛋白质被转运到细胞质中以被泛素-蛋白酶体系统降解。ER 常驻 E3 泛素连接酶 HRD1 已被确定为一个关键的 ERAD 因子，它直接催化泛素缀合到未折叠或错误折叠的蛋白质上以进行蛋白酶体降解。在类风湿滑膜细胞中发现了异常增加的 HRD1 表达，为 HRD1 失调参与人类炎症发病机制提供了第一个证据。进一步的研究表明，参与类风湿发病机制的炎性细胞因子包括 IL-1β、TNF-α、IL-17 和 IL-26 诱导 HRD1 表达。最近使用具有组织特异性靶向缺失 HRD1 基因的小鼠的研究揭示了 HRD1 在免疫调节和炎症性疾病中的重要功能。HRD1 已被证明对于 CD4 和 CD8 T 细胞的抗原的树突状细胞表达至关重要。TCR 和共刺激受体 CD28 信号传导均诱导 HRD1 表达，从而促进 T 细胞克隆扩增和 IL-2 产生。连同 HRD1 是维持调节性 T 细胞 (Treg) 稳定性所必需的事实，HRD1 似乎可以微调 T 细胞免疫。此外，HRD1 通过调节早期 B 细胞发育和识别特定抗原后维持 B 细胞存活而参与体液免疫反应。HRD1 似乎通过依赖 ERAD 或不依赖 ERAD 来靶向其泛素化底物，至少两种不同的分子机制以细胞或组织特异性方式实现其生理功能。HRD1 表达和/或其功能的失调涉及自身免疫性炎性疾病，特别是类风湿性关节炎和狼疮。在这里，我们回顾了目前关于 HRD1 蛋白在免疫调节中的机制以及 HRD1 参与自身免疫性炎症性疾病发病机制的研究结果。