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The generation of large numbers of plasma cells (PCs) is a main factor in systemic lupus erythematosus (SLE). We hypothesize that Hspa13, a member of the heat shock protein family, plays a critical role in the control of PC differentiation. To test the hypothesis, we used lipopolysaccharide (LPS)-activated B cells and a newly established mouse line with a CD19 cre -mediated, B cell-specific deletion of Hspa13: Hspa13 cKO mice. We found that Hspa13 mRNA was increased in PCs from atacicept-treated lupus-prone mice and in LPS-stimulated plasmablasts (PBs) and PCs. A critical finding was that PBs and PCs [but not naïve B cells and germinal center (GC) B cells] expressed high levels of Hspa13. In contrast, the Hspa13 cKO mice had a reduction in BPs, PCs, and antibodies induced in vitro by LPS and in vivo by sheep red blood cells (SRCs)- or 4-hydroxy-3-nitrophenylacetyl (NP)-immunization. Accordingly, the Hspa13 cKO mice had reduced class-switched and somatically hypermutated antibodies with defective affinity maturation. Our work also showed that Hspa13 interacts with proteins (e.g., Bcap31) in the endoplasmic reticulum (ER) to positively regulate protein transport from the ER to the cytosol. Importantly, Hspa13 mRNA was increased in B220 + cells from patients with multiple myeloma (MM) or SLE, whereas Hspa13 cKO led to reduced autoantibodies and proteinuria in both pristane-induced lupus and lupus-prone MRL/lpr mouse models. Collectively, our data suggest that Hspa13 is critical for PC development and may be a new target for eliminating pathologic PCs., (Copyright © 2020 He, Xu, Zhai, Fang, Hou, Xing, Xiao, Chen, Wang, Ma, Han and Wang.)

Multiple myeloma (MM) results from biased proliferation of cancerous plasma cells (PC). Therapeutic strategies that target MM PC will provide immense value to the treatment of MM. For this, it is necessary to identify novel molecules that differ between MM PC and healthy PC. RNA sequencing was used to determine differences in gene expression profiles between LPS-induced plasmablasts (PB)/PC and the PB-like myeloma SP 2/0 cell line. Compared to LPS-induced PB/PC, SP 2/0 cells expressed significantly lower levels of Loc108167440 mRNA. Loc108167440 overexpression reduced the number of SP 2/0 cells by stimulating apoptotic cell death. In addition, Loc108167440 overexpression suppressed tumor progression in the SP 2/0 xenograft mouse model. Finally, we demonstrated that Loc108167440 overexpression up-regulated expression of p53 in SP 2/0 cells. These results suggest that Loc108167440 overexpression suppressed SP 2/0 cell growth by inducing p53-mediated apoptosis. Thus, Loc108167440 overexpression may be a potential therapy for treating MM.

Cell apoptosis plays a critical role in initiation and progression of tumor and autoimmune diseases, resistance and susceptibility to various therapeutic agents. Our previous study showed that metabotropic glutamate receptor 3 (Grm3) may be involved in autoreactive B-cell apoptosis in a B-cell-depleted agent atacicept-treated lupus-like mice. In the present study, we explore whether Grm3 is involved in the apoptosis in B-cell-related tumor including multiple myeloma and B-cell leukemia. We found that human B-cell leukemia cell line Nalm-6 cells and mouse myeloma cell line SP 2/0 cells could express Grm3. In addition, Grm3 expression emerged mainly in the middle stage of Nalm-6 and SP 2/0 cell apoptosis. Furthermore, apoptosis-induced agents effectively upregulated Grm3 expression in SP 2/0 cells. Critically, Grm3 deficiency promoted tumor progression in an SP 2/0 xenograft mouse model by suppressing cell apoptosis, whereas Grm3 overexpression effectively upregulates SP 2/0 cell apoptosis. Finally, we showed that Grm3 mediated cell apoptosis by Foxo1. Together, our data suggest that Grm3 effectively suppresses the mouse myeloma cell line SP 2/0 cell growth by mediating apoptosis. Thus, Grm3 may be used as an indicator in apoptosis of B-cell-related tumor and a potential target for the treatment of B-cell-related tumor including multiple myeloma and B-cell leukemia.