BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation

Our plain-English summary of BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation, by A. Bononi, C. Giorgi, S. Patergnani, et al (Nature, 2017).

The study

• Authors: A. Bononi, C. Giorgi, S. Patergnani, D. Larson, K. Verbruggen, M. Tanji, L. Pellegrini, V. Signorato, F. Olivetto, S. Pastorino, M. Nasu, A. Napolitano, G. Gaudino, P. Morris, G. Sakamoto, L.K. Ferris, A. Danese, A. Raimondi, C. Tacchetti, S. Kuchay, H.I. Pass, E.B. Affar, H. Yang, P. Pinton, M. Carbone
• Journal: Nature
• Published: 2017;546(7659):549-553
• Cited by: 339 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1+/-) developed one and often several BAP1-/- malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1+/- carriers cause reduction both of IP3R3 levels and of Ca2+ flux, preventing BAP1+/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1+/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.

In plain English

This laboratory study, published as a letter, used cultured cells and did not measure disease in people. The authors grew skin cells from seven carriers of an inherited BAP1 mutation (W and L families) and seven age- and gender-matched non-carrier relatives. They also used human mesothelial cells and cell lines. Carriers' cells had about 50% of the normal amount of BAP1 protein. BAP1 was found at the endoplasmic reticulum, where it bound and stabilized a calcium channel, IP3R3. Carriers' cells had less IP3R3, released less calcium, and resisted cell death from several drugs. After radiation they repaired DNA less well, yet more of them survived. After the same UVA or UVB dose, carriers' cells formed 24% and 132% more colonies, respectively, than relatives' cells. Mesothelial cells with reduced BAP1 or IP3R3 exposed to crocidolite asbestos had lower calcium levels and resisted cell death. In mesothelial cells exposed to crocidolite with TNF-alpha, reducing BAP1 significantly increased foci formation, the authors' measure of cell transformation. The authors proposed that carriers' high cancer rate results from combined reduced BAP1 activity in the nucleus and cytoplasm.

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 (in vitro) study of cultured cells: primary skin fibroblasts from mutation carriers and matched relatives, primary human mesothelial cells with BAP1 or IP3R3 experimentally reduced, cell lines, and mouse fibroblasts
• Who was studied: Skin fibroblasts from 14 adult volunteers in the W (Wisconsin) and L (Louisiana) families: seven carriers of an inherited heterozygous BAP1 mutation and seven age- and gender-matched non-carrier relatives. Also primary human mesothelial cells from three donors with non-malignant conditions, malignant mesothelioma cell lines, HEK293 and THP-1 cells, and fibroblasts from Bap1 heterozygous and wild-type mice.
• Exposure: Crocidolite asbestos at 5 micrograms per square centimetre (glass or PBS as controls), given in the transformation assay together with TNF-alpha. Also ionizing radiation, UVA and UVB at 25 mJ per square centimetre, and drugs that induce cell death (hydrogen peroxide, C2-ceramide, menadione, 5-fluorouracil).
• Main results:
  • Fibroblasts from BAP1 mutation carriers contained about 50% of the BAP1 protein found in cells from non-carrier relatives.
  • Outside the nucleus, BAP1 was found specifically in the endoplasmic reticulum fraction of the cells tested.
  • All seven carrier fibroblast cultures were more resistant to several cell-death-inducing drugs than the seven matched non-carrier cultures.
  • Carrier fibroblasts had reduced levels of the IP3R3 protein compared with non-carrier fibroblasts.
  • Carrier fibroblasts released less calcium from the endoplasmic reticulum than non-carrier fibroblasts.
  • Carrier fibroblasts survived ionizing radiation better than non-carrier fibroblasts in clonogenic assays, despite a reduced ability to repair the DNA damage it caused.
  • After 25 mJ per square centimetre of UVA or UVB, carrier fibroblasts formed more colonies than matched control fibroblasts given the same exposure: a 24% increase with UVA and a 132% increase with UVB.
  • Human mesothelial cells with BAP1 or IP3R3 silenced and exposed to crocidolite had lower intracellular calcium concentrations, and were resistant to cell death, compared with control cells.
  • In a transformation assay in which primary human mesothelial cells were exposed to crocidolite in the presence of TNF-alpha, cells with BAP1 silenced showed a significant increase in foci formation.
  • Silencing IP3R3 increased foci formation less than silencing BAP1.
  • In BAP1-silenced mesothelial cells, a form of BAP1 confined to the cytoplasm significantly reduced foci formation, to levels similar to those obtained with normal BAP1.
• The authors' conclusion: The authors proposed that the high incidence of cancers in carriers of inherited BAP1 mutations results from the combined reduced activities of BAP1 in the nucleus and in the cytoplasm.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Carcinogenesis, Malignant Mesothelioma, Apoptosis.

Related studies

• Germline BAP1 mutations induce a Warburg effect — A. Bononi, H. Yang, et al. (2017)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy — J. Xue, S. Patergnani, et al. (2020)
• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling — F. Novelli, Y. Yoshikawa, et al. (2024)
• Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity — M. Bocchetta, I. Di Resta, et al. (2000)
• High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma — M. Nasu, M. Emi, et al. (2015)

Browse more research in Nature, or return to medical research.