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Brain-specific angiogenesis inhibitor 1 (BAI1) is a transmembrane protein with anti-angiogenic activity.
Interaction of brain-specific angiogenesis inhibitor 1 with bacteria triggers pro-inflammatory responses
The emerging role of BAI1 as a potential pattern recognition receptor (PRR) for Gram-negative bacteria has caused a special interest in BAI family members for their innate immunity and inflammation. Studies involving BAI1 depleted macrophages showed abnormally reduced levels of tumor necrosis factor production when stimulated by LPS or Gram-negative bacteria, suggesting that BAI1 may have a significant contribution in pro-inflammatory responses. Activities of BAI1 associated with detection of a key PAMP like LPS seemingly suggest its probable role in pro-inflammatory response similar to pattern recognition receptors (PRRs)–induced inflammation. This pro-inflammatory response plays a key role in the early detection of Gram-negative pathogens, immune activation and clearance, and subsequently aids adaptive immunity, and LPS is a major virulence factor for many types of gram-negative pathogens.
Currently, in macrophages and dendritic cells, Toll-like receptor (TLR)-4 is primarily responsible for the detection of bacterial LPS that triggers pro-inflammatory cytokine production and other inflammatory immune responses. In these cells, TLR-4 and co-receptors MD2 and CD14 can detect lipids. Interestingly, it has been found that the BAI1 TSRs can recognize and directly interact with LPS, which can internalization of gram-negative pathogen. A recent study showed that BAI1 is involved in the phagocytic uptake of Gram-negative bacteria as a PRR, and promotes the activation of NADPH oxidase activity in macrophages by activating the Rho1-dependent pathway of the Rho family GTPase, promoting phagosome reactive oxygen species. The authors have implemented a peritoneal infection model involving BAI1-deficient mice to demonstrate the novel properties of BAI1 in coupling bacterial assays to cell sterilization machinery. However, the underlying role of BAI1 as a PRR and the underlying mechanism of potential crosstalk between BAI1 and TLR4 is unclear.
Brain-specific angiogenesis inhibitor 1 and tumorigenesis
Abnormal expression of BAI1 protein is associated with the development of several malignancies. Significant down-regulation of BAI1 mRNA levels was observed in lung adenocarcinoma, primary glioma specimens, and advanced brain tumors. Studies on normal bladder mucosal biopsy specimens of bladder transitional cell carcinoma indicate that BAI1 is a negative regulator of microvascular proliferation with decreased BAI1 expression in progressive cancer samples.
In contrast, exogenous recovery of BAI1 expression has been reported to reduce tumor proliferation and angiogenesis associated with glioma and renal cancer. Many studies have shown that BAI1 expression is absent, defective or highly reduced in most human glioma cell lines and primary glioblastoma samples, thereby inhibiting its anti-tumorigenic activity. Changes in the p53 gene are associated with angiogenesis, a key step for glioma to enter glioblastoma. Although P53 is an important member of the tumor suppressor gene family, it is the most common mutated gene in human cancers. It was found that the expression of wild-type p53 mediated by adenovirus transfection can reconstitute the loss of BAI1 expression in a series of human cancer cell lines. Zhu et al, demonstrated that BAI1 regulates the normal development of cerebellum and prevents the transformation of neural progenitor cells during EGL amplification. BAI1 plays a suppressor tumor in MB, and it is an upstream protector of p53. Reveal that alteration in ADGRB1/BAI1 represents a point of vulnerability in cancer. BAI1 as a protective agent for p53 tumor suppressor, which is consistent with previous studies, the loss of p53 increased penetrance and accelerated tumor formation in the mouse MB model. BAI1 protects p53 by binding Mdm2, the p53 E3 ubiquitin ligase, thereby reduces its nuclear level and stabilizes p53. Taken together, these results define the BAI1-P53 signal axis and show its importance in brain tumorigenesis. Although most of the MB lacks the p53 mutation, approximately 40% of the macroblocks exhibit dysfunctional p53 target gene expression, suggesting that other mechanisms can abolish the tumor monitoring activity of p53.
Fig. 1. BAI1 inhibits tumorigenesis by preventing p53 from Mdm2-Mediated Degradation. (Zhu et al., 2018, Cancer Cell).
BAI1 as an engulfment receptor for apoptotic cells
BAI1 is increasingly recognized for its role in the phagocytosis of apoptotic cells which is mainly mediated by ELMO1/Dock/Rac1 signaling module. The ELMO1/Dock pathway finally leads to activation of small GTPase Rac proteins. The activity of Rac is critical for rapid actin remodeling and membrane trafficking during phagocytosis of apoptotic cells. The BAI1 receptor has also been identified as activating cytoskeletal recombination, involving the Rho pathway activated by Gα-dependent mechanisms. It is known that Helicobacter pylori or camptothecin induces apoptosis in gastric epithelial cells. A recent study showed a significant increase in BAI1 expression in peripheral blood mononuclear cell-derived macrophages or THP-1 cells, which is associated with increased binding and clearance of apoptotic epithelial cells by these gastric phagocytic cells. Previous studies have shown that the dual function of BAI1 as an apoptotic phagocytic receptor and an anti-angiogenic factor is based on their origin. In general, glial-derived BAI1 can be used for phagocytic function in adult brain regions (e.g., olfactory bulbs, which typically have high apoptotic turnover), and facial neuron-derived BAI1 acts as an anti-angiogenic factor in mature neuropil. Generally, macrophages are known to uptake large amounts of cholesterol during the removal of apoptotic cells. BAI1 has recently been associated with upregulation of ATP-binding cassette transporters (ABAC1), a vital protein for cholesterol efflux in macrophages. This suggests an important role for BAI1 in the membrane initiation pathway triggered by apoptotic cells.
Fig. 2. BAI1 as the receptor upstream of the ELMO1/Dock180/Rac1 module. (Penberthy et al. Immunol Rev. 2016)