Human canonical CD157/Bst1 is an alternatively spliced isoform masking a previously unidentified primate-specific exon included in a novel transcript

Our plain-English summary of Human canonical CD157/Bst1 is an alternatively spliced isoform masking a previously unidentified primate-specific exon included in a novel transcript, by E. Ferrero, N. Lo Buono, S. Morone, et al (Scientific Reports, 2017).

The study

• Authors: E. Ferrero, N. Lo Buono, S. Morone, R. Parrotta, C. Mancini, A. Brusco, A. Giacomino, S. Augeri, A. Rosal-Vela, S. García-Rodríguez, M. Zubiaur, J. Sancho, A. Fiorio Pla, A. Funaro
• Journal: Scientific Reports
• Published: 2017;7(1):15923
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

CD157/Bst1 is a dual-function receptor and β-NAD+-metabolizing ectoenzyme of the ADP-ribosyl cyclase family. Expressed in human peripheral blood neutrophils and monocytes, CD157 interacts with extracellular matrix components and regulates leukocyte diapedesis via integrin-mediated signalling in inflammation. CD157 also regulates cell migration and is a marker of adverse prognosis in epithelial ovarian cancer and pleural mesothelioma. One form of CD157 is known to date: the canonical sequence of 318 aa from a 9-exon transcript encoded by BST1 on human chromosome 4. Here we describe a second BST1 transcript, consisting of 10 exons, in human neutrophils. This transcript includes an unreported exon, exon 1b, located between exons 1 and 2 of BST1. Inclusion of exon 1b in frame yields CD157-002, a novel proteoform of 333 aa: exclusion of exon 1b by alternative splicing generates canonical CD157, the dominant proteoform in neutrophils and other tissues analysed here. In comparative functional analyses, both proteoforms were indistinguishable in cell surface localization, specific mAb binding, and behaviour in cell adhesion and migration. However, NAD glycohydrolase activity was detected in canonical CD157 alone. Comparative phylogenetics indicate that exon 1b is a genomic innovation acquired during primate evolution, pointing to the importance of alternative splicing for CD157 function.

In plain English

This was a laboratory study of the human gene BST1, which makes a cell-surface protein called CD157. The authors tested white blood cells (neutrophils) from 10 healthy adults and a leukaemia cell line. They found a previously unrecognised 45-base-pair piece of the gene, which they named exon 1b. When this piece is included, cells make a longer form of the protein, CD157-002 (333 amino acids), instead of the known 318-amino-acid form. In neutrophils, the usual form made up about 75–80% of the two gene messages combined. The authors also used HeLa cells engineered to carry one form or the other. Compared with the usual form, CD157-002 helped cells stick to fibronectin and type I collagen more strongly and, with serum present, move more efficiently. Both differences were statistically significant. However, CD157-002 lacked the usual form's NAD-breaking enzyme activity. Exon 1b-like sequences were found only in primates, in 11 species. The authors concluded that their findings add complexity to studies of CD157 in human disease. The study did not examine asbestos exposure or people with mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study (molecular biology, cell experiments and database analysis of gene sequences)
• Who was studied: Neutrophils (polymorphonuclear leukocytes) from 10 healthy adults; the THP1 monocytic leukaemia cell line; a commercial panel of normal human tissue RNA; HeLa cells engineered to express each CD157 form; gene databases for primate and other species
• Main results:
  • A previously unrecognised 45 bp piece of the BST1 gene (named exon 1b) was found between exons 1 and 2 in the gene message from THP1 cells and neutrophils.
  • Including exon 1b produces a longer protein, CD157-002, of 333 amino acids. Skipping it produces the usual (canonical) CD157 of 318 amino acids.
  • In neutrophils from 10 healthy adults, the usual BST1-001 message was always more abundant than BST1-002, making up about 75–80% of the two combined.
  • In engineered HeLa cells, those carrying CD157-002 bound fibronectin and type I collagen more efficiently than those carrying the usual CD157 (reported as statistically significant, p less than 0.001).
  • With 10% serum present, HeLa cells carrying CD157-002 migrated more efficiently than cells carrying the usual CD157 (p less than 0.01). Without serum, migration of the two was similar.
  • HeLa cells carrying the usual CD157 showed NAD glycohydrolase (NADase) enzyme activity. Cells carrying CD157-002 gave a negligible signal.
  • In the cyclase assay using NGD+ as a substitute substrate, results were almost negative for both forms of CD157.
  • Database searches found sequences resembling exon 1b in 11 species, all primates. None were found in tarsier, lemuriforms, mouse or rat.
• The authors' conclusion: The authors concluded that their findings add a new level of complexity to analyses of CD157's relevance to human disease and to its evaluation as a treatment target. They also concluded that functional experiments will reflect the relative contribution of the two protein forms.
• Limitations the authors state:
  • The authors' 3D protein model did not explain why CD157-002 lost its NADase activity.
  • CD157-002 may have other functional properties that the assays used could not detect.
  • Database information for Old and New World monkeys was less informative, so the role of exon 1b in these species was still being studied.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Prognosis, Ovarian Cancer, Pleural Mesothelioma.

Related studies

• CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome — E. Ortolan, A. Giacomino, et al. (2014)
• CD157: From immunoregulatory protein to potential therapeutic target — E. Ortolan, S. Augeri, et al. (2019)
• Differentially expressed alternatively spliced genes in malignant pleural mesothelioma identified using massively parallel transcriptome sequencing — L. Dong, R.V. Jensen, et al. (2009)
• Exon deletion in the MSLN gene encoding MPF/mesothelin precursor protein during Laurasiatherian mammal evolution — D.S. Kim, Y. Hahn (2011)
• Asbestos Exposure in Patients with Malignant Pleural Mesothelioma included in the PRIMATE Study, Lombardy, Italy — A. Spinazzè, D. Consonni, et al. (2022)
• Tumorigenic properties of alternative osteopontin isoforms in mesothelioma — S.V. Ivanov, A.V. Ivanova, et al. (2009)

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