BNIP3 is degraded by ULK1-dependent autophagy via MTORC1 and AMPK

Park, Chang Wook; Sun, Hao; Kim, Eung-Sam; Kwon, Jung Hyeok; Kim, Kyong‐Tai; Nam, Hong Gil; Choi, Kwan Yong

doi:10.4161/auto.23072

Cited by 58 publications

(41 citation statements)

References 52 publications

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“…Additionally, starvation-induced autophagy in the heart (Zhu et al 2007) and skeletal muscle (Mammucari et al 2007) has been demonstrated in the absence of changes to Beclin1. Bnip3, whose expression is mainly under transcriptional control by HIF-1a (Gustafsson 2011), can be degraded during starvation-induced autophagy (Park et al 2013). However, we observed decreased Bnip3 in SHR soleus, a muscle which did not display significant alterations in other autophagy markers.…”

Section: Discussioncontrasting

confidence: 59%

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Autophagy is altered in skeletal and cardiac muscle of spontaneously hypertensive rats

et al. 2013

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Section: Discussioncontrasting

confidence: 59%

“…Bnip3, whose expression is mainly under transcriptional control by HIF‐1α (Gustafsson ), can be degraded during starvation‐induced autophagy (Park et al . ). However, we observed decreased Bnip3 in SHR soleus, a muscle which did not display significant alterations in other autophagy markers.…”

Section: Discussionmentioning

confidence: 97%

Autophagy is altered in skeletal and cardiac muscle of spontaneously hypertensive rats

et al. 2013

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“…As a result, the tunicamycin-induced expression of Bnip3 mRNA was comparable in both cell types (Figure 4D), raising the possibility that the accumulation of Bnip3 protein in Ire1α knockout MEFs might be due to delayed protein degradation. Bnip3 protein turnover can be regulated by autophagy (29, 30). IRE1α-mediated activation of JNK induces cytoprotective autophagy under ER stress conditions, and suppression of autophagy can render cells susceptible to death triggered by ER stress (31, 32).…”

Section: Resultsmentioning

confidence: 99%

IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions

Kanekura

Murphy

et al. 2015

Sci. Signal.

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The endoplasmic reticulum (ER) has emerged as a critical regulator of cell fate. IRE1 is a transmembrane protein with kinase and RNase activities that is localized to the ER and that promotes resistance to ER stress. Here we showed a mechanism by which IRE1 conferred protection against ER stress-mediated cell death. IRE1 signaling prevented ER membrane permeabilization mediated by Bax and Bak and cell death under ER stress conditions. Suppression of IRE1 signaling led to the accumulation of the BH3 domain-containing protein Bnip3, which in turn triggered the oligomerization of Bax and Bak in the ER membrane and ER membrane permeabilization. As a result, cells deficient in IRE1 were susceptible to leakage of ER contents in response to ER stress, which was associated with the accumulation of calcium in mitochondria, oxidative stress in the cytosol, and cell death. Our results reveal a role for IRE1 in preventing an initial step of cell death emanating from the ER and provide a potential target for treating diseases characterized by ER stress, including diabetes and Wolfram syndrome.

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“…It may be significant, therefore, that TPC2 gating and thus autophagy may be modulated by mTOR [31, 67]. This may well speak to further roles for lysosomal calcium signaling and L-SR junctional plasticity during hypoxic pulmonary vasoconstriction and even during the development of hypoxia pulmonary hypertension [68], not least because AMP-activated protein kinase has been shown to modulate autophagy through the phosphorylation and inhibition of mTOR (see for example, [69]).…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic nanojunctions between lysosomes and sarcoplasmic reticulum are required for specific calcium signaling

Fameli

Ogunbayo

Breemen

et al. 2014

Preprint

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Herein we demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) serve to couple lysosomal activation to regenerative, ryanodine receptormediated cellular Ca 2+ waves. In pulmonary artery smooth muscle cells (PASMCs) it has been proposed that nicotinic acid adenine dinucleotide phosphate (NAADP) triggers increases in cytoplasmic Ca 2+ via L-SR junctions, in a manner that requires initial Ca 2+ release from lysosomes and subsequent Ca 2+ -induced Ca 2+ release (CICR) via ryanodine receptor (RyR) subtype 3 on the SR membrane proximal to lysosomes. L-SR junction membrane separation has been estimated to be < 400 nm and thus beyond the resolution of light microscopy, which has restricted detailed investigations of the junctional coupling process. The present study utilizes standard and tomographic transmission electron microscopy to provide a thorough ultrastructural characterization of the L-SR junctions in PASMCs. We show that L-SR nanojunctions are prominent features within these cells and estimate that the junctional membrane separation and extension are about 15 nm and 300 nm, respectively. Furthermore, we develop a quantitative model of the L-SR junction using these measurements, prior kinetic and specific Ca 2+ signal information as input data. Simulations of NAADP-dependent junctional Ca 2+ transients demonstrate that the magnitude of these signals can breach the threshold for CICR via RyR3. By correlation analysis of live cell Ca 2+ signals and simulated Ca 2+ transients within L-SR junctions, we estimate that "trigger zones" with a 60-100 junctions are required to confer a signal of similar magnitude. This is compatible with the 130 lysosomes/cell estimated from our ultrastructural observations. Most importantly, our model shows that increasing the L-SR junctional width above 50 nm lowers the magnitude of junctional [Ca 2+ ] such that there is a failure to breach the threshold for CICR via RyR3. L-SR junctions are therefore a pre-requisite for efficient Ca 2+ signal coupling and may contribute to cellular function in health and disease.

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BNIP3 is degraded by ULK1-dependent autophagy via MTORC1 and AMPK

Cited by 58 publications

References 52 publications

Autophagy is altered in skeletal and cardiac muscle of spontaneously hypertensive rats

Autophagy is altered in skeletal and cardiac muscle of spontaneously hypertensive rats

IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions

Cytoplasmic nanojunctions between lysosomes and sarcoplasmic reticulum are required for specific calcium signaling

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