Cyclosporine A suppresses immunoglobulin G biosynthesis via inhibition of cyclophilin B in murine hybridomas and B cells.
Immunoglubulin G (IgG) is a major isotype of antibody, which is predominantly involved in immune response. The complete tetramer is needed to fold and assemble in endoplasmic reticulum (ER) prior to secretion from cells. Protein quality control guided by ER chaperons is most essential for full biological activity. Cyclophilin B (CypB) was initially identified as a high-affinity binding protein for the immunosuppressive drug Cyclosporine A (CsA). CsA suppresses organ rejection by halting productions of pro-inflammatory molecules in T cell and abolishes the enzymatic property of CypB that accelerates the folding of proteins by catalysing the isomerization of peptidyl-proline bonds in ER. Here, we reported that CsA significantly inhibited IgG biosynthesis at posttranslational level in antibody secreting cells. Moreover, CsA stimulated the extracellular secretion of CypB and induced ROS generation, leading to expressions of ER stress markers. In addition, the absence of intracellular CypB impaired the formation of ER multiprotein complex, which is most important for resisting ER stress. Interestingly, CsA interrupted IgG folding via occupying the PPIase domain of CypB in ER. Eventually, unfolded IgG is degraded via Herp-dependent ERAD pathway. Furthermore, IgG biosynthesis was really abrogated by inhibition of CypB in primary B cells. We established for the first time the immunosuppressive effect of CsA on B cells. Conclusively, the combined results of the current study suggest that CypB is a pivotal molecule for IgG biosynthesis in ER quality control.
Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Dongdaemoon-gu, Seoul, Republic of Korea.
Jisun
J
Lee
Tae Gyu
TG
Choi
Joohun
J
Ha
Sung Soo
SS
Kim
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006825:Hybridomas / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C053387:endoplasmin; C081786:cyclophilin B; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D005982:Glutathione Transferase; D021983:Cyclophilins