Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins

Abstract

The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drives human pathologies, including cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the proper culling of cells during normal eukaryotic development and the maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 (B Cell Lymphoma 2) family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between the BCL-2 proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small molecule modulators of apoptosis are now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.

Autophagy-Independent Functions of the Autophagy Machinery

“…Nonetheless, there is a general tendency to attribute unique functions to specific proteins, often reflecting the earliest or most abundant literature on the topic. As an example, while caspase 3 (CASP3) is globally recognized as a key effector in apoptosis (Galluzzi et al, 2018a;Singh et al, 2019), its non-apoptotic role in the differentiation of multiple cell types (Nakajima and Kuranaga, 2017) is largely underappreciated. The same issue applies to hundreds other proteins that have been characterized mostly, if not only, in the context of a single cellular process, including multiple components of the molecular machinery for macroautophagy.…”

Pleiotropy of Bcl-2 family proteins is an ancient trait in the metazoan evolution

“…[4][5][6][7] . These proteins contain one to four B-cell homology domains, as well as a hydrophobic C-terminus transmembrane domain 8 . Although the control of apoptosis differs substantially between roundworms, insects and mammals, seminal experiments conducted in these models reinforced the dogma that Bcl-2 family of proteins were evolutionary selected to control the survival of the cell at the level of the mitochondria.…”

Cofilin‐1–induced actin reorganization in stored platelets

“…6 The BCL family has three functional groups: antiapoptotic proteins (e.g., Bcl-2, Bcl-1xL), proapoptotic effectors (e.g., Bax, Bak), and proapoptotic activators (e.g., Bid, Bad). 7 During mitochondrial pathway of apoptosis, proapoptotic Bax and Bak translocate to the mitochondrial membrane and induce the permeabilization of the mitochondrial membrane and release of cytochrome c. Bcl-xL prevents apoptosis by sequestering Bax. Bcl-xL deficiency causes thrombocytopenia by shortening platelet life span in vivo.…”