Fig. 1

Diagram showing the regulation of chronic inflammation and cell transformation by the BAP1, HDAC1, and HMGB1 trimer. Asbestos causes mesothelial cell death that in turn leads to the release of HMGB1 from the nucleus to the extracellular space, where HMGB1 acts as a DAMP recruiting macrophages and other inflammatory cells. Macrophages actively secrete HMGB1 and TNF-α propagating inflammation around asbestos deposits in tissue, a process that over time can cause malignant transformation and mesothelioma. A similar process takes place in mesothelial cells carrying germline BAP1 mutations (BAP1^+/−), depicted at the bottom of the figure, even in the absence of asbestos exposure. In BAP1 wild-type (WT) cells, nuclear BAP1 deubiquitylates and stabilizes HDAC1, which deacetylates HMGB1: deacetylated HMGB1 remains in the nucleus. In BAP1^+/− cells, the reduced BAP1 levels cause HDAC1 ubiquitylation and degradation. This, in turn, causes increased acetylation of HMGB1. Acetylated HMGB1 moves to the cytoplasm where it activates autophagy, and from there to the extracellular space where HMGB1 propagates chronic information that favors malignant transformation and mesothelioma growth. The combination of asbestos exposure and BAP1 germline mutations can cooperate in propagating chronic inflammation and malignant transformation [21]. Created with BioRender.com