The B cell lymphoma 2 (BCL2) protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria. In this cutting-edge review, we summarize the basic biology regulating the BCL2 family including canonical and non-canonical functions, and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions. We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and tools targeting the BH4 domain of BCL2. The first BCL2-selective BH3-mimetic, venetoclax, showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies. Following its success, several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation, alone and in combination. Genetic analysis highlights the importance of BCL-X_L and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-X_L or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-X_L and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-X_L or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy. Taken together, we envision that the targeting of BCL2 proteins, while already a success story of translational research, may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.

The endoplasmic reticulum (ER) as an intracellular Ca²⁺ store not only sets up cytosolic Ca²⁺ signals, but, among other functions, also assembles and folds newly synthesized proteins. Alterations in ER homeostasis, including severe Ca²⁺ depletion, are an upstream event in the pathophysiology of many diseases. On the one hand, insufficient release of activator Ca²⁺ may no longer sustain essential cell functions. On the other hand, loss of luminal Ca²⁺ causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death. We will review these various diseases by mainly focusing on the mechanisms that cause ER Ca²⁺ depletion.

Ionized calcium (Ca²⁺) is the most versatile cellular messenger. All cells use Ca²⁺ signals to regulate their activities in response to extrinsic and intrinsic stimuli. Alterations in cellular Ca²⁺ signaling and/or Ca²⁺ homeostasis can subvert physiological processes into driving pathological outcomes. Imaging of living cells over the past decades has demonstrated that Ca²⁺ signals encode information in their frequency, kinetics, amplitude, and spatial extent. These parameters alter depending on the type and intensity of stimulation, and cellular context. Moreover, it is evident that different cell types produce widely varying Ca²⁺ signals, with properties that suit their physiological functions. This primer discusses basic principles and mechanisms underlying cellular Ca²⁺ signaling and Ca²⁺ homeostasis. Consequently, we have cited some historical articles in addition to more recent findings. A brief summary of the core features of cellular Ca²⁺ signaling is provided, with particular focus on Ca²⁺ stores and Ca²⁺ transport across cellular membranes, as well as mechanisms by which Ca²⁺ signals activate downstream effector systems.

Although the presence of a BH4 domain distinguishes the antiapoptotic protein Bcl-2 from its proapoptotic relatives, little is known about its function. BH4 deletion converts Bcl-2 into a proapoptotic protein, whereas a TAT-BH4 fusion peptide inhibits apoptosis and improves survival in models of disease due to accelerated apoptosis. Thus, the BH4 domain has antiapoptotic activity independent of full-length Bcl-2. Here we report that the BH4 domain mediates interaction of Bcl-2 with the inositol 1,4,5-trisphosphate (IP3) receptor, an IP3-gated Ca ²⁺ channel on the endoplasmic reticulum (ER). BH4 peptide binds to the regulatory and coupling domain of the IP3 receptor and inhibits IP3-dependent channel opening, Ca ²⁺ release from the ER, and Ca ²⁺ -mediated apoptosis. A peptide inhibitor of Bcl-2-IP3 receptor interaction prevents these BH4-mediated effects. By inhibiting proapoptotic Ca ²⁺ signals at their point of origin, the Bcl-2 BH4 domain has the facility to block diverse pathways through which Ca ²⁺ induces apoptosis.