BAP1 and PTEN Stabilize IP3R3 to Promote Ca²⁺-Mediated Apoptosis

The type 3 inositol-1,4,5-triphosphate receptor (IP3R3) controls calcium (Ca²⁺) release from the endoplasmic reticulum (ER) to the mitochondria. Persistent Ca²⁺ release overloads the mitochondria and results in apoptosis. Related studies identified two tumor suppressor proteins, BAP1 and PTEN, that promote IP3R3-mediated Ca²⁺ flux to promote apoptosis and suppress oncogenic transformation. Bononi and colleagues found that BAP1 binds to and deubiquitinates IP3R3 at the ER, thereby stabilizing IP3R3, enhancing Ca²⁺ flux, and promoting apoptosis. BAP^+/− fibroblasts exhibited reduced IP3R3 protein levels, decreased mitochondrial Ca²⁺ uptake, and reduced apoptosis compared to wild-type fibroblasts. BAP1 also exhibited nuclear activity, and BAP1 depletion impaired DNA damage repair, resulting in enhanced DNA damage. Although these cells accumulated increased DNA damage, they could not execute apoptosis due to reduced mitochondrial Ca²⁺. In primary human mesothelial cells, asbestos exposure promoted malignant transformation, which was increased by depletion of IP3R3 or BAP1, although BAP1 depletion had a stronger effect due to its additional nuclear function. Kuchay, Giorgi, and colleagues found that PTEN also prevents IP3R3 degradation. Mechanistically, PTEN competed with FBXL2 for IP3R3 binding, and, as FBXL2 promoted proteasome-mediated degradation of IP3R3, PTEN binding stabilized IP3R3. FBXL2 depletion increased Ca²⁺ release from the ER and sensitized cells to apoptosis. Conversely, PTEN loss promoted FBXL2-mediated degradation of IP3R3, and PTEN reconstitution, irrespective of its phosphatase activity, stabilized IP3R3 to induce Ca²⁺ mobilization and apoptosis. Moreover, expression of PTEN and IP3R3 were correlated in human prostate cancer. In prostate cancer xenografts, a nondegradable IP3R3 mutant or an inhibitor that disrupted FBXL2 membrane localization sensitized tumors expressing low levels of PTEN to photodynamic therapy, which induces Ca²⁺-dependent cytotoxicity. Taken together, these studies elucidate mechanisms by which BAP1 or PTEN stabilize IP3R3 to promote mitochondrial Ca²⁺ overload and apoptosis, thereby limiting tumor growth. These findings suggest the possibility for drugs that stabilize IP3R3 to treat BAP1- or PTEN-deficient tumors.

Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, et al. BAP1 regulates IP3R3-mediated Ca²⁺ flux to mitochondria suppressing cell transformation. Nature 2017;546:549–53.

Kuchay S, Giorgi C, Simoneschi D, Pagan J, Missiroli S, Saraf A, et al. PTEN counteracts FBXL2 to promote IP3R3- and Ca²⁺-mediated apoptosis limiting tumour growth. Nature 2017;546:554–8.

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