Abstract
Bcl-2 associated athanogene 3 (BAG3) contains multiple protein-binding motifs to mediate potential interactions with chaperons and/or other proteins, which is possibly ascribed to the multifaceted functions assigned to BAG3. The current study demonstrated that BAG3 directly interacted with glucose 6 phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). BAG3 suppressed the PPP flux, de novo DNA synthesis and cell growth in hepatocellular carcinomas (HCCs). The growth defect of HCCs with forced BAG3 expression can be rescued by enforced G6PD expression. However, BAG3 elevation did not cause a reduction in cellular NADPH concentrations, another main product of G6PD. In addition, supplement of nucleosides alone was sufficient to recover the growth defect mediated by BAG3 elevation. Collectively, the current study established a tumor suppressor-like function of BAG3 via direct interaction with G6PD in HCCs at the cellular level.
Highlights
Bcl-2 associated athanogene (BAG) proteins share evolutionarily conserved BAG domain at their C-terminus, through which BAG proteins interact with ATPase domain of Hsc/Hsp70 family [38]
One of mechanisms used by cells to support the rapid proliferation is redirection of glucose toward the phosphate pathway (PPP), which may protect cells from reactive oxygen species (ROS) by generation of the reduced form of glutathione using nicotinamide adenine dinucleotide phosphate (NADPH) [3]
The current study demonstrated that Bcl-2 associated athanogene 3 (BAG3) directly interacted with glucose 6 phosphate dehydrogenase (G6PD) (Figure 1) and suppressed G6PD activity in hepatocellular carcinomas (HCCs) (Figure 2B)
Summary
Bcl-2 associated athanogene (BAG) proteins share evolutionarily conserved BAG domain at their C-terminus, through which BAG proteins interact with ATPase domain of Hsc/Hsp family [38]. Beside conserved BAG domain, BAG3 contains multiple protein binding motifs to mediate potential interactions with chaperons and/or other proteins: a WW domain at the N-terminus, a proline-rich region (PxxP) in the central region, two IPV motifs (Ile-ProVal) between the WW domain and the PxxP region [10]. Normal cells except for myocytes seldom express BAG3, while its expression can be induced in many cell types in response to cell stress [11, 30, 42]. BAG3 induction is believed to serve as a protective mechanism upon cellular stress [6, 18, 25, 36,37,38, 42]. BAG3 protein appears to exert pro-survival and anti-apoptotic roles, as its reduction promotes apoptosis of various cancer cells [4, 22,23,24, 27,28,29, 31, 36, 42, 43]
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