Alternative titles; symbols
HGNC Approved Gene Symbol: MZB1
Cytogenetic location: 5q31.2 Genomic coordinates (GRCh38) : 5:139,387,467-139,389,913 (from NCBI)
Using dominant-negative caspase-2 (CASP2; 600639) as bait in a yeast 2-hybrid screen of a B-cell cDNA library, followed by 5-prime RACE, Bonfoco et al. (2001) cloned PACAP. The deduced 123-amino acid protein has a calculated molecular mass of 13.6 kD. PACAP contains a leucine-rich N-terminal signal sequence with a cleavage site following residue 22, 2 possible myristoylation sites, a glycosaminoglycan attachment site, and several putative phosphorylation sites. It also has sequences that share homology with several motifs, including the WD40 motif, ATP/GTP-binding site motif A, cytochrome c (CYC; 123970)-binding site, glycoprotease family signature, and serine protease active site. Semiquantitative PCR detected highest PACAP expression in adult brain, with intermediate to low expression in all other tissues tested except placenta and fetal brain. Immunofluorescence localization detected PACAP in a granular distribution in the cytosol surrounding the nucleus in transfected human embryonic kidney cells and rat fibroblasts.
By database analysis, Katoh and Katoh (2003) identified MGC29506 as a splice variant of PACAP. The deduced 189-amino acid MGC29506 protein is identical to PACAP in the first 59 amino acids, but the proteins diverge in the C-terminal region due to a frameshift caused by a 16-bp insertion in the PACAP cDNA. EST database analysis indicated that MGC29506 is the major transcript. Katoh and Katoh (2003) identified MGC29506 homologs in several other species, and the N-terminal signal peptide, 6 cysteine residues, and other amino acids were conserved.
By screening cDNA clones of pre-B cells minus an erythroid subtractive cDNA library for expression in follicular B cells, marginal zone (MZ) B cells, and B1 cells, Flach et al. (2010) identified Mzb1, which was expressed primarily in MZ B cells and B1 cells, with much less expression in follicular B cells. Mzb1 encodes a conserved protein of 188 amino acids with an N-terminal signal sequence, a CxxC thioredoxin motif at position 49, and a C-terminal endoplasmic reticulum (ER) retrieval sequence. Northern blot analysis of adult mouse tissues revealed predominant expression in lymph nodes and spleen. Cell fractionation and immunohistochemical analysis of mouse B cells and fibroblasts showed localization of Mzb1 in the ER lumen.
Using in vitro protein binding assays and Western blot analysis, Bonfoco et al. (2001) found that PACAP interacted with CASP2 and CASP9 (602234), but not with other caspases, in Jurkat human T-cells. Immunoprecipitation analysis confirmed interaction between PACAP and CASP2 and CASP9. Mutation analysis indicated that the caspase-binding site resides between residues 39 to 72 of PACAP. Overexpression of PACAP in human embryonic kidney cells, human B-cell lines, and rat fibroblasts induced apoptosis. In addition, endogenous PACAP was dramatically downregulated in primary human B cells early after ligand-stimulated activation, and it was upregulated during apoptosis.
Flach et al. (2010) found that downregulation or overexpression of mouse Mzb1 in mouse MZ and follicular B cells increased or decreased cell proliferation, respectively. Flow cytometric and immunofluorescence microscopy demonstrated that Mzb2 expression decreased luminal ER Ca(2+) store content. ELISA showed that Mzb1 regulated antibody secretion by MZ B cells, but not follicular B cells. Mzb1 interacted with Grp94 (HSP90B1; 191175) and regulated the integrin-folding activity mediated by ERp57 (PDIA3; 602046). Flach et al. (2010) concluded that MZB1 helps to diversify peripheral B-cell functions by regulating Ca(2+) stores, antibody secretion, and integrin activation.
Katoh and Katoh (2003) determined that the MZB1 gene contains 4 exons.
Katoh and Katoh (2003) mapped the MZB1 gene to chromosome 5q31.2.
Bonfoco, E., Li, E., Kolbinger, F., Cooper, N. R. Characterization of a novel proapoptotic caspase-2- and caspase-9-binding protein. J. Biol. Chem. 276: 29242-29250, 2001. [PubMed: 11350957] [Full Text: https://doi.org/10.1074/jbc.M100684200]
Flach, H., Rosenbaum, M., Duchniewicz, M., Kim, S., Zhang, S. L., Cahalan, M. D., Mittler, G., Grosschedl, R. Mzb1 protein regulates calcium homeostasis, antibody secretion, and integrin activation in innate-like B cells. Immunity 33: 723-735, 2010. [PubMed: 21093319] [Full Text: https://doi.org/10.1016/j.immuni.2010.11.013]
Katoh, M., Katoh, M. MGC29506 gene, frequently down-regulated in intestinal-type gastric cancer, encodes secreted-type protein with conserved cysteine residues. Int. J. Oncol. 23: 235-241, 2003. [PubMed: 12792799]