title: Sil1, a nucleotide exchange factor for BiP, is not required for antibody assembly or secretion.
abstract: Sil1 is a nucleotide exchange factor for the endoplasmic reticulum chaperone BiP, and mutations in this gene lead to Marinesco-Sjögren syndrome (MSS), a debilitating autosomal recessive disease characterized by multisystem defects. A mouse model for MSS was previously produced by disrupting Sil1 using gene-trap methodology. The resulting Sil1Gt mouse phenocopies several pathologies associated with MSS, although its ability to assemble and secrete antibodies, the best-characterized substrate of BiP, has not been investigated. In vivo antigen-specific immunizations and ex vivo LPS stimulation of splenic B cells revealed that the Sil1Gt mouse was indistinguishable from wild-type age-matched controls in terms of both the kinetics and magnitude of antigen-specific antibody responses. There was no significant accumulation of BiP-associated Ig assembly intermediates or evidence that another molecular chaperone system was used for antibody production in the LPS-stimulated splenic B cells from Sil1Gt mice. ER chaperones were expressed at the same level in Sil1WT and Sil1Gt mice, indicating that there was no evident compensation for the disruption of Sil1. Finally, these results were confirmed and extended in three human EBV-transformed lymphoblastoid cell lines from individuals with MSS, leading us to conclude that the BiP cofactor Sil1 is dispensable for antibody production.
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN 38163.
authors.forename: Viraj P
authors.initials: VP
authors.lastname: Ichhaporia
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN 38163.
authors.forename: Tyler
authors.initials: T
authors.lastname: Sanford
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Jenny
authors.initials: J
authors.lastname: Howes
authors.affiliation: Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN 38163.
authors.forename: Tony N
authors.initials: TN
authors.lastname: Marion
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105; linda.hendershot@stjude.org.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Hendershot
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D002461:Cell Line, Transformed; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009154:Mutation; D013132:Spinocerebellar Degenerations / Q000235:genetics / Q000276:immunology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; C418483:SIL1 protein, human; C000594797:SIL1 protein, mouse