Icariin Induces Synoviolin Expression through NFE2L1 to Protect Neurons from ER Stress-Induced Apoptosis

By suppressing neuronal apoptosis, Icariin is a potential therapeutic drug for neuronal degenerative diseases. The molecular mechanisms of Icariin anti-apoptotic functions are still largely unclear. In this report, we found that Icariin induces the expression of Synoviolin, an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis. The nuclear factor erythroid 2-related factor 1 (NFE2L1) is responsible for Icariin-mediated Synoviolin gene expression. Mutation of the NFE2L1-binding sites in a distal region of the Synoviolin promoter abolished Icariin-induced Synoviolin promoter activity, and knockdown of NFE2L1 expression prevented Icariin-stimulated Synoviolin expression. More importantly, Icariin protected ER stress-induced apoptosis of PC12 cells in a Synoviolin-dependent manner. Therefore, our study reveals Icariin-induced Synoviolin expression through NFE2L1 as a previously unappreciated molecular mechanism underlying the neuronal protective function of Icariin.     

Essential role of synoviolin in embryogenesis

We recently reported the importance of Synoviolin in quality control of proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) system and its involvement in the pathogenesis of arthropathy through its anti-apoptotic effect. For further understanding of the role of Synoviolin in vivo, we generated in this study synoviolin-deficient (syno(-/-)) mice by genetargeted disruption. Strikingly, all fetuses lacking syno died in utero around embryonic day 13.5, although Hrd1p, a yeast orthologue of Synoviolin, is non-essential for survival. Histologically, hypocellularity and aberrant apoptosis were noted in the syno(-/-) fetal liver. Moreover, definitive erythropoiesis was affected in non-cell autonomous manner in syno(-/-) embryos, causing death in utero. Cultured embryonic fibroblasts derived from syno(-/-) mice were more susceptible to endoplasmic reticulum stress-induced apoptosis than those from syno(+/+) mice, but the susceptibility was rescued by overexpression of synoviolin. Our findings emphasized the indispensable role of the Synoviolin in embryogenesis.     

The Roles of Synoviolin in Crosstalk Between Endoplasmic Reticulum Stress-Induced Apoptosis and p53 Pathway

Endopalsmic reticulum (ER) is specialized organelle to maintain the integrity of secreted and membranous proteins. ER also senses so-called “ER stress”, which is a resulted from a various internal and external stresses, and triggers apoptosis when the diverse attempts to accommodate with the stress are in fail. The impairment these ER functions has been implicated in several human diseases, in which aberrant ER stress induced apoptosis is observed. We discuss about another disease model related with ER mediated apoptosis based on the recent studies about Synoviolin, an E3 ubiquitin ligase inherently utilized for ER associated degradation (ERAD). In addition to its canonical role in ERAD, Synoviolin targets tumor suppressor gene p53 for proteasomal degradation, suggesting the crosstalk between ERAD and p53 mediated apoptotic pathway under ER stress. Together with the anti-apoptotic property of Synoviolin previously elucidated by both in vitro and in vivo analyses, its new function in p53 regulation may provide a new insight into the pathomechanism of proliferative diseases such as cancer or rheumatoid arthritis.     

Rheumatoid arthritis as a hyper-endoplasmic reticulum-associated degradation disease

We introduce Synoviolin as a novel pathogenic factor in rheumatoid arthritis (RA). Experimental studies indicate that this endoplasmic reticulum (ER)-resident E3 ubiquitin ligase has important functions in the ER-associated degradation (ERAD) system, an essential system for ER homeostasis. Overexpression of Synoviolin in mice causes arthropathy with synovial hyperplasia, whereas heterozygous knockdown results in increased apoptosis of synovial cells and resistance to collagen-induced arthritis in mice. On the basis of these experimental data, we propose that excess elimination of unfolded proteins (that is, 'hyper-ERAD') by overexpression of Synoviolin triggers synovial cell overgrowth and hence a worsening of RA. Further analysis of the hyper-ERAD system may permit the complex pathomechanisms of RA to be uncovered.