Endoplasmic reticulum-associated degradation and beyond: The multitasking roles for HRD1 in immune regulation and autoimmunity.

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.