BAD Is a Pro-survival Factor Prior to Activation of Its Pro-apoptotic Function

Abstract

The mammalian BAD protein belongs to the BH3-only subgroup of the BCL-2 family. In contrast to its known pro-apoptotic function, we found that endogenous and overexpressed BAD L can inhibit cell death in neurons and other cell types. Several mechanisms regulate the conversion of BAD from an anti-death to a pro-death factor, including alternative splicing that produces the N-terminally truncated BAD S . In addition, caspases convert BAD L into a pro-death fragment that resembles the short splice variant. The caspase site that is selectively cleaved during cell death following growth factor (interleukin-3) withdrawal is conserved between human and murine BAD. A second cleavage site that is required for murine BAD to promote death following Sindbis virus infection, ␥-irradiation, and staurosporine treatment is not conserved in human BAD, consistent with the inability of human BAD to promote death with these stimuli. However, loss of the BAD N terminus by any mechanism is not always sufficient to activate its pro-death activity, suggesting that the N terminus is a regulatory domain rather than an anti-death domain. These findings suggest that BAD is more than an inert death factor in healthy cells; it is also a pro-survival factor, prior to its role in promoting cell death.

Mitochondrial factors with dual roles in death and survival

“…If true, this would support a model suggesting that all pro-death factors also have pro-survival 'day jobs' (Figure 1). Consistent with this idea, but contrary to the norm, endogenous Bax, Bak and Bad are potent anti-death (not pro-death) factors in some scenarios (Lewis et al, 1999;Fannjiang et al, 2003;Seo et al, 2004). For example, hippocampal neurons and spinal cord motor neurons in Bak-deficient mice, and their derived tissues, are significantly more susceptible to cell death triggered by excitotic agents and neurotropic viruses.…”

“…However, Bid also needs to be activated in cells by proteolytic cleavage or in vitro by detergent-induced conformational changes. In fact, a number of Bcl-2 family proteins are cleaved by caspases and other proteases to alter their functions (Cheng et al, 1997;Clem et al, 1998;Kirsch et al, 1999;Seo et al, 2004). Other BH3-only proteins, such as Bad, are suggested to directly bind and inactivate the anti-death Bcl-2 family proteins (Puthalakath et al, 1999;Cheng et al, 2001;Wei et al, 2001).…”

Exposure to Hypoxia Rapidly Induces Mitochondrial Channel Activity within a Living Synapse

“…It is known that cleavage of several BCL-2 family proteins, including BCL-xL, by proteases during programmed cell death enhances or activates their pro-death function (33)(34)(35)(36)(37)(38)(39)(40). In the squid stellate ganglion, we showed previously that hypoxia induces proteolysis of native BCL-xL and that a proteolytic fragment of this protein produces large conductance channel activity when applied to mitochondrial membranes (24).…”

Alternate functions of viral regulators of cell death

“…For example, Bax, Bak and Bad can be antiapoptotic, 15,61,62 whereas Bcl-2 and Bcl-x L can promote cell death when their N-terminus is cleaved off. [63][64][65] An extensive analysis of Bak knockout mice revealed that Bak function is dependent on the cell type, the developmental stage and the specific death stimulus.…”

“…This antideath function of Bad was gradually lost relative to matched controls over the next few weeks, but was repeatedly recovered by generating new cell lines (SY Seo and JM Hardwick, unpublished). 62 Similarly, cIAP1 function must be analyzed de novo (T-T Sheu and JM Hardwick, unpublished). However, by considering the nature of these compensatory mutations that permit survival and growth in the absence of antideath factors, we will likely learn about the underlying functions of viral antideath factors.…”