BAX Inhibitor-1 Is a Negative Regulator of the ER Stress Sensor IRE1α

Lisbona, Fernanda; Rojas‐Rivera, Diego; Thielen, Peter; Zamorano, Sebastián; Todd, Derrick J.; Martinon, Fabio; Glavic, Álvaro; Kress, Christina L.; Lin, Jonathan H.; Walter, Peter; Reed, John C.; Glimcher, Laurie H.; Hetz, Claudio

doi:10.1016/j.molcel.2009.02.017

Cited by 284 publications

(321 citation statements)

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“…Importantly, BiP was unchanged (Supplementary Figure 3a). Despite the role of BI-1 as a direct inhibitor of IRE1α, 14 we observed decreased XBP-1 splicing in KO cells (Supplementary Figure 3b) in line with the decreased expression of ER stress-regulated chaperones. We concluded that the UPR and the ER overload reactions are not constitutively active in splenocytes isolated directly from BI-1 KO mice.…”

Section: Resultsmentioning

confidence: 62%

“…This was later reproduced and attributed to an inhibitory function of BI-1 on IRE1α mediated via a direct interaction of the two proteins. 14 In our study, we found that bi-1 − / − mice are more obese and suffer from leukopenia. T and B cells from these mice show significant changes in cellular Ca 2+ homeostasis and dynamics, and are more prone to spontaneous death in culture but, surprisingly, demonstrate no signs of ongoing ER stress within the homeostatic system of the living animal.…”

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confidence: 50%

“…14 IRE1α not only interacts with BI-1 but also with the proapoptotic proteins BAX and BAK (Bcl-2 homologous antagonist/killer), which in contrast to BI-1 activate IRE1α signaling. 37 Cells lacking both proteins have a reduced ER Ca 2+ concentration 38 because of an increased Ca 2+ leak 39 and therefore behave like BI-1-overexpressing cells.…”

Section: Discussionmentioning

confidence: 99%

“…37 Cells lacking both proteins have a reduced ER Ca 2+ concentration 38 because of an increased Ca 2+ leak 39 and therefore behave like BI-1-overexpressing cells. 7 As BI-1 does not directly interact with BAX/BAK 5,14 but attenuates the interaction of BAX with IRE1α, 14 it was speculated that BI-1 acts upstream of these proteins in the control of IRE1α inactivation. 14 However, maybe the proposed inactivation of IRE1α by BI-1 is reciprocal, meaning that IRE1α also inhibits BI-1 channel activity.…”

Section: Discussionmentioning

confidence: 99%

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BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

et al. 2015

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The endoplasmic reticulum (ER) serves as the major intracellular Ca 2+ store and has a role in the synthesis and folding of proteins. BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is a Ca 2+ leak channel also implicated in the response against protein misfolding, thereby connecting the Ca 2+ store and protein-folding functions of the ER. We found that BI-1-deficient mice suffer from leukopenia and erythrocytosis, have an increased number of splenic marginal zone B cells and higher abundance and nuclear translocation of NF-κB (nuclear factor-κ light-chain enhancer of activated B cells) proteins, correlating with increased cytosolic and ER Ca 2+ levels. When put into culture, purified knockout T cells and even more so B cells die spontaneously. This is preceded by increased activity of the mitochondrial initiator caspase-9 and correlated with a significant surge in mitochondrial Ca 2+ levels, suggesting an exhausted mitochondrial Ca 2+ buffer capacity as the underlying cause for cell death in vitro. In vivo, T-cell-dependent experimental autoimmune encephalomyelitis and B-cell-dependent antibody production are attenuated, corroborating the ex vivo results. These results suggest that BI-1 has a major role in the functioning of the adaptive immune system by regulating intracellular Ca 2+ homeostasis in lymphocytes. Cell Death and Differentiation (2016) 23, 358-368; doi:10.1038/cdd.2015; published online 16 October 2015The endoplasmic reticulum (ER) serves as the major intracellular calcium (Ca 2+ ) store, the release of which controls a vast array of cellular functions from short-term responses such as contraction and secretion to long-term regulation of cell growth and proliferation. 1 Dysregulated release of ER Ca 2+ , in contrast, initiates programmed cell death by several mechanisms including mitochondrial Ca 2+ overload, depolarization, ATP loss and cytochrome c release. 2 Besides this, the ER also has a key role in the synthesis, folding and sorting of proteins destined for the secretory pathway. The deleterious consequences of an increase in unfolded proteins is called ER stress and can be antagonized by the unfolded protein response (UPR), a mechanism that coordinates a simultaneous increase in the ER folding capacity and a decrease in folding load. In the case of insufficient adaptation to ER stress, cells undergo apoptosis. 3 BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is an evolutionarily conserved protein that bridges both the Ca 2+ homeostasis and UPR functions of the ER. 4 BI-1 was first identified in a screen for human proteins capable of inhibiting BAX-mediated cell death in yeast. 5 In mammalian cells, BI-1's antiapoptotic function is most pronounced in paradigms of ER stress 6 and involves changes in the amount of Ca 2+ that can be released from intracellular stores. 6,7 BI-1 is a highly hydrophobic protein that forms a Ca 2+ pore responsible for its Ca 2+ leak properties 8 and is the founding member of a family of six proteins with similar properties. 9 The increase in the ER Ca 2+ lea...

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Section: Resultsmentioning

confidence: 62%

mentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

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“…38 IRE1 forms protein-protein interactions with BCL2 family proteins, such as BAX and BAK, and the BI-1 BCL2 regulatory protein. 39,40 IRE1 also binds cytoskeletal nonmuscle myosin II during ER stress. 41 XBP1s RIDD Normal Acute Phase Chronic Phase…”

Section: Upr In Disease Pathogenesismentioning

confidence: 99%

Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

Hiramatsu

Chiang

Kurt

et al. 2015

The American Journal of Pathology

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Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease

2010

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Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning public health concernin westernized nations. The obesity-related disorder is associated with an increased risk of cardiovascular disease, type 2 diabetes and liver failure. Although the underlying pathogenesis of NAFLD is unclear, increasing evidence suggests that excess saturated fatty acids presented to or stored within the liver may play a role in both the development and progression of the disorder. Aputative mechanism linking saturated fatty acids to NAFLD may been doplasmic reticulum (ER) stress. Specifically, excess saturated fatty acids may induce an ER stress response that, if left unabated, can activate stress signaling pathways, cause hepatocyte cell death, and eventually lead to liver dysfunction. In the current review we discuss the involvement of saturated fatty acids in the pathogenesis of NAFLD with particular emphasis on the role of ER stress.

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BAX Inhibitor-1 Is a Negative Regulator of the ER Stress Sensor IRE1α

Cited by 284 publications

References 47 publications

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease

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