In conclusion, IRE1α appears to mediate early processes in B cell maturation, particularly in connection with VDJ rearrangement [91] [92]. To evaluate the role of IRE1α in plasma cell differentiation, Zhang and collaborators used IRE1Α dominant-negative mutants [91]. B cells

expressing RNAse- or kinase- dominant-negative mutants of IRE1α, or cells lacking the intracytoplasmic tail were unable to secrete immunoglobulins. When these cells were transduced with XBP-1s and stimulated with LPS, immunoglobulin secretion was restored in the RNAse- or kinase- dominant-negative mutants expressing cells. In contrast, the cells lacking the cytoplasmic tail of IRE1α did not restored immunoglobulin secretion when transduced with XBP-1s. Thus, IRE1α cytoplasmic Cabozantinib region have another role in addition to its catalytic activity in antibody production, perhaps acting as a scaffold for other proteins [91]. XBP-1 conditional knockout mice (XBP1flox/floxCD19cre/+) were generated to answer the question of whether XBP-1 altered the formation of memory B cells. XBP-1-deficient B cells were able to differentiate into post-GC memory B cells (IgDloB220+CD138−) and preplasma memory B cells (IgDloB220loCD79b+CD138−) in vivo, but no plasma cell was encountered in these mice [93]. Interestingly, XBP1flox/floxCD19cre/+ mice were protected against systemic

lupus erythematosus [59, 93]. Murine splenic B cells and I.29 B cell lymphoma were stimulated with LPS or treated with tunicamycin, followed by chromatin precipitation. XBP-1 was found bound to the ERDJ3 promoter in association with enhanced find more ERDJ3 transcription [94]. ERdj3 is a co-chaperone that associates with BiP/IgH complexes [20]. Furthermore, XBP-1 indirectly regulates IgH expression by controlling transcription of OBF1, which codes for a specific IgH transcriptional co-activator. XBP-1 binds to the OBF1 promoter, possibly through an ACGT/C sequence found in human and mice OBF1 promoters [94]. These are

the first evidences that demonstrate XBP-1 acting directly on target gene promoter during plasma cell differentiation [20, 94]. During the plasmacytic differentiation programme the PERK branch of the UPR and its downstream targets are silenced [91, 95, 96]. Two independent studies provided evidences that the IRE1/XBP-1, but not PERK/eIF2α, from axis of UPR was activated in B lymphocytes after LPS treatment [91, 95]. Interestingly, B lymphocyte maturation occurred normally in PERK-deficient animals and their B cells could differentiate into plasma cells and secrete antibodies [95]. A third study showed that under LPS induced differentiation, I.29 μ+ B cell line activated IRE1α and consequently spliced XBP-1 mRNA at early phases. PERK was partially phosphorylated, but the LPS-elicited PERK activation was insufficient to phosphorylate eIF2α and to induce GADD34 and CHOP, downstream events of PERK activation. Curiously, pretreatment of I.