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Ubiquitin Ligases and Posttranslational Regulation of Energy in the Heart: The Hand that Feeds

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ABSTRACT

Heart failure (HF) is a costly and deadly syndrome characterized by the reduced capacity of the heart to adequately provide systemic blood flow. Mounting evidence implicates pathological changes in cardiac energy metabolism as a contributing factor in the development of HF. While the main source of fuel in the healthy heart is the oxidation of fatty acids, in the failing heart the less energy efficient glucose and glycogen metabolism are upregulated. The ubiquitin proteasome system plays a key role in regulating metabolism via protein‐degradation/regulation of autophagy and regulating metabolism‐related transcription and cell signaling processes. In this review, we discuss recent research that describes the role of the ubiquitin‐proteasome system (UPS) in regulating metabolism in the context of HF. We focus on ubiquitin ligases (E3s), the component of the UPS that confers substrate specificity, and detail the current understanding of how these E3s contribute to cardiac pathology and metabolism. © 2017 American Physiological Society. Compr Physiol 7:841‐862, 2017.

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Figure 1. Figure 1. Ubiquitin chains and the 26S proteasome. Monoubiquitination and multimonoubiquitination (multiple monoubiquitinations of the same protein) regulate diverse protein functions including transcriptional regulation, subcellular localization, protein‐protein interactions, membrane internalization, chromatin remodeling and DNA damage repair. K48‐ and K11‐linked polyubiquitination targets substrates for degradation by the 26S proteasome. K63‐linked ubiquitin chains have been implicated in autophagy, protein recruitment, and membrane internalization (). Other polyubiquitin chain types have been identified (K6, K27, K29, K33), but their functions are still unclear. The proteasome is a large protein complex composed of a lid, 19S regulatory proteins and a 20S core particle which together forms the 26S proteasome. Polyubiquitin chains (K48, K11) are recognized by ubiquitin shuttling receptors that assist with the entry of the substrate into the 26S proteasome for degradation.
Figure 2. Figure 2. MuRF1 regulates PPARα and downstream metabolic signaling by monoubiquitination. Activation of PPARα by endogenous (FA) or exogenous (Fibrates) agonists results in binding to the PPAR Response Element (PPRE) with its coactivator RXR and transcription of target genes such as: ACO, CYP4A, FABP, ADRP, ApoA, and PDK4 (). This results in enhanced FA metabolism and inhibition of glucose metabolism. Additional anti‐inflammatory effects are due to repression of NFκB (). MuRF1 inhibits PPARα transcriptional activity by monoubiquitination, which results in nuclear export ().
Figure 3. Figure 3. The role of thyroid hormone in regulating energy metabolism and the potential significance of cardiac ubiquitin ligases in regulating these pathways. The thyroid plays an important role in regulating energy metabolism through the action of thyroid hormone(s) it releases, where it acts on peripheral tissues such as the heart, skeletal muscle, and liver (). Thyroid hormone acts upon some thyroid receptors, including the thyroid hormone receptor α (TRα) and thyroid receptor beta (TRβ). The TRα1 and TRβ1 are predominantly involved in the heart and skeletal muscle metabolic control, in addition to other peripheral tissues [as recently reviewed by ()]. (A) TRs hetero‐dimerize with the retinoic acid receptor (RXR) and can homo‐dimerize and interact with other nuclear receptors (e.g., PPARα). Coactivators also regulate TRs, such as the sirtuin SIRT1 (). Some of the thyroid hormone effects on SIRT1 require TRβ to TREs (). Importantly, FOXO1 is a target gene regulated by the T3‐TRβ‐SIRT1 action (). Deacetylation induces gluconeogenesis gene expression in mice that do not contain TRE in their promoters (). (B) Nongenomic thyroid hormone actions are present on the plasma membrane, where the thyroid hormone T4 interacts with the αvβ3 integrin (). (C) Thyroid hormone stimulates mitochondrial respiration (), in studies primarily in liver (). (D) T3 rapidly activates mTOR in a TRβ1 and Akt/PKB‐dependent manner to influences the transcription of genes involved in glucose metabolism, including HIF‐1α and its downstream targets GLUT1, PFKP, and MCT4 involved in glucose uptake (GLUT1), glycolysis (PFKP), and lactate export (MCT4) (), as seen in studies of pancreatic, fibroblast, adipocyte, and neuronal mitochondria (). (E) Thyroid hormone enhances mitochondrial uncoupling by its regulation of mitochondrial uncoupling proteins (UCPs). Specifically, thyroid hormone binding to TRβ increases mitochondrial UCP1 and UCP2 (adipocytes and neurons) (). While this is likely via activation of mTor/Akt, this link has not been directly shown in the heart (dashed line). (F) T3 regulates mitophagy (mitochondrial autophagy) in an ROS‐and oxidative phosphorylation‐dependent manner to regulate the removal of damaged mitochondria (in studies of liver mitochondria) (). T3 induced ROS activate CAMKK2 and AMPK, which then activates ULK1 (unc‐51‐like autophagy activating kinase 1), leading to the recruitment of mitochondria and initiation of mitophagy (in liver mitochondria) (). (G) A parallel process of replacing mitochondria called mitochondrial biogenesis is also regulated by thyroid hormone, and may be induced to balance the removal of mitochondria by mitophagy. Recent studies have found that T3‐mediated stimulation of PGC‐1 induced mitochondrial protein expression to induce mitochondrial biogenesis (). (H) Thyroid hormone enhances AMPK activity, to affect both lipid and glucose metabolism (in liver mitochondria) (), while T3 enhances AMPK activation/phosphorylation (Thr172), which then phosphorylates and inactivates acetyl‐CoA carboxylase (ACC) (in osteoclasts, hepatocytes, neurons, cardiomyocyte mitochondria) (). T3’s inactivation of ACC enhances the reaction necessary for lipids to be transported into the mitochondria via CPT1, resulting in increased lipid oxidation and decreased lipid storage (). Activated AMPK enhances glucose uptake and reduces metabolism to play an important role in the pathogenesis of diabetic cardiomyopathy (). Therefore, thyroid hormone activity in the heart regulates both glucose and lipid metabolism through its regulation of T3‐AMPK in the heart. Red arrows: Negative effects on metabolism. Black arrows: Positive effects on metabolism. **MuRF1 Inhibits these activities (,). *MuRF1 found here; specific substrates not validated (). Original representation of data concepts from: Senese, et al., 2014 (), Mihaylova and Shaw 2011 () and Lopez, et al., 2013 ().
Figure 4. Figure 4. CHIP is necessary for AMPK activity. CHIP/Stub1 acts as a chaperone of AMPK, an important metabolic sensor and stress response mediator (). AMPK activity is notably increased in models of cardiac hypertrophy, hypoxia and ischemia (). CHIP is necessary for AMPK activity, even when it is in its phosphorylated state. AMPK activity supports oxidative phosphorylation and lipid metabolism to increase ATP ().


Figure 1. Ubiquitin chains and the 26S proteasome. Monoubiquitination and multimonoubiquitination (multiple monoubiquitinations of the same protein) regulate diverse protein functions including transcriptional regulation, subcellular localization, protein‐protein interactions, membrane internalization, chromatin remodeling and DNA damage repair. K48‐ and K11‐linked polyubiquitination targets substrates for degradation by the 26S proteasome. K63‐linked ubiquitin chains have been implicated in autophagy, protein recruitment, and membrane internalization (). Other polyubiquitin chain types have been identified (K6, K27, K29, K33), but their functions are still unclear. The proteasome is a large protein complex composed of a lid, 19S regulatory proteins and a 20S core particle which together forms the 26S proteasome. Polyubiquitin chains (K48, K11) are recognized by ubiquitin shuttling receptors that assist with the entry of the substrate into the 26S proteasome for degradation.


Figure 2. MuRF1 regulates PPARα and downstream metabolic signaling by monoubiquitination. Activation of PPARα by endogenous (FA) or exogenous (Fibrates) agonists results in binding to the PPAR Response Element (PPRE) with its coactivator RXR and transcription of target genes such as: ACO, CYP4A, FABP, ADRP, ApoA, and PDK4 (). This results in enhanced FA metabolism and inhibition of glucose metabolism. Additional anti‐inflammatory effects are due to repression of NFκB (). MuRF1 inhibits PPARα transcriptional activity by monoubiquitination, which results in nuclear export ().


Figure 3. The role of thyroid hormone in regulating energy metabolism and the potential significance of cardiac ubiquitin ligases in regulating these pathways. The thyroid plays an important role in regulating energy metabolism through the action of thyroid hormone(s) it releases, where it acts on peripheral tissues such as the heart, skeletal muscle, and liver (). Thyroid hormone acts upon some thyroid receptors, including the thyroid hormone receptor α (TRα) and thyroid receptor beta (TRβ). The TRα1 and TRβ1 are predominantly involved in the heart and skeletal muscle metabolic control, in addition to other peripheral tissues [as recently reviewed by ()]. (A) TRs hetero‐dimerize with the retinoic acid receptor (RXR) and can homo‐dimerize and interact with other nuclear receptors (e.g., PPARα). Coactivators also regulate TRs, such as the sirtuin SIRT1 (). Some of the thyroid hormone effects on SIRT1 require TRβ to TREs (). Importantly, FOXO1 is a target gene regulated by the T3‐TRβ‐SIRT1 action (). Deacetylation induces gluconeogenesis gene expression in mice that do not contain TRE in their promoters (). (B) Nongenomic thyroid hormone actions are present on the plasma membrane, where the thyroid hormone T4 interacts with the αvβ3 integrin (). (C) Thyroid hormone stimulates mitochondrial respiration (), in studies primarily in liver (). (D) T3 rapidly activates mTOR in a TRβ1 and Akt/PKB‐dependent manner to influences the transcription of genes involved in glucose metabolism, including HIF‐1α and its downstream targets GLUT1, PFKP, and MCT4 involved in glucose uptake (GLUT1), glycolysis (PFKP), and lactate export (MCT4) (), as seen in studies of pancreatic, fibroblast, adipocyte, and neuronal mitochondria (). (E) Thyroid hormone enhances mitochondrial uncoupling by its regulation of mitochondrial uncoupling proteins (UCPs). Specifically, thyroid hormone binding to TRβ increases mitochondrial UCP1 and UCP2 (adipocytes and neurons) (). While this is likely via activation of mTor/Akt, this link has not been directly shown in the heart (dashed line). (F) T3 regulates mitophagy (mitochondrial autophagy) in an ROS‐and oxidative phosphorylation‐dependent manner to regulate the removal of damaged mitochondria (in studies of liver mitochondria) (). T3 induced ROS activate CAMKK2 and AMPK, which then activates ULK1 (unc‐51‐like autophagy activating kinase 1), leading to the recruitment of mitochondria and initiation of mitophagy (in liver mitochondria) (). (G) A parallel process of replacing mitochondria called mitochondrial biogenesis is also regulated by thyroid hormone, and may be induced to balance the removal of mitochondria by mitophagy. Recent studies have found that T3‐mediated stimulation of PGC‐1 induced mitochondrial protein expression to induce mitochondrial biogenesis (). (H) Thyroid hormone enhances AMPK activity, to affect both lipid and glucose metabolism (in liver mitochondria) (), while T3 enhances AMPK activation/phosphorylation (Thr172), which then phosphorylates and inactivates acetyl‐CoA carboxylase (ACC) (in osteoclasts, hepatocytes, neurons, cardiomyocyte mitochondria) (). T3’s inactivation of ACC enhances the reaction necessary for lipids to be transported into the mitochondria via CPT1, resulting in increased lipid oxidation and decreased lipid storage (). Activated AMPK enhances glucose uptake and reduces metabolism to play an important role in the pathogenesis of diabetic cardiomyopathy (). Therefore, thyroid hormone activity in the heart regulates both glucose and lipid metabolism through its regulation of T3‐AMPK in the heart. Red arrows: Negative effects on metabolism. Black arrows: Positive effects on metabolism. **MuRF1 Inhibits these activities (,). *MuRF1 found here; specific substrates not validated (). Original representation of data concepts from: Senese, et al., 2014 (), Mihaylova and Shaw 2011 () and Lopez, et al., 2013 ().


Figure 4. CHIP is necessary for AMPK activity. CHIP/Stub1 acts as a chaperone of AMPK, an important metabolic sensor and stress response mediator (). AMPK activity is notably increased in models of cardiac hypertrophy, hypoxia and ischemia (). CHIP is necessary for AMPK activity, even when it is in its phosphorylated state. AMPK activity supports oxidative phosphorylation and lipid metabolism to increase ATP ().
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Teaching Material

D. I. Brown, T. L. Parry, M. S. Willis. Ubiquitin Ligases and Posttranslational Regulation of Energy in the Heart: The Hand that Feeds. Compr Physiol 7 2017, 841-862.

Didactic Synopsis

Major Teaching Points:

     

  1. The ubiquitin-proteasome system regulates energy metabolism in the heart in physiological and pathophysiological conditions
  2.  

     

  3. Both cardiac specific and ubiquitously expressed ubiquitin ligases contribute to heart failure associated metabolic effects
  4.  

     

  5. Targeting ubiquitin ligases therapeutically could have beneficial effects in the context of heart disease
  6.  

Didactic Legends

The figures-in a freely downloadable PowerPoint format-can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

 

Figure 1. Teaching points: This figure shows the variety of different types of ubiquitination, and its known function. Monoubiquitination has been implicated in regulating protein function and localization. Canonical polyubiquitination of proteins (K48, K11) results in recognition and degradation by the 26S proteasome. Other orientations of polyubiquitination (K6, K27, K29, K33) have been identified but their function is unknown or multifaceted.

 

Figure 2. Teaching points: Fatty acid energy metabolism provides the majority of ATP in the heart. PPARα in the nucleus transcriptionally activates genes involved in fatty acid metabolism, and repress genes that regulate the less efficient glucose oxidation pathways. MuRF1 initiates the nuclear export of PPARα via monoubiquitination, which switches energy metabolism to more heavily favor glucose.


 

Figure 3. Teaching points: MuRF family proteins regulate fatty acid and glucose metabolism in direct ways, which several likely indirect regulatory pathways. MuRF1 directly regulates PPARalpha (and therefore lipid/glucose metabolism); at the same time, MuRF1's regulation of TRalpha likely has multiple indirect effects on lipid metabolism. Based on TRalpha's well-known signaling pathways in noncardiomyocyte cells/organs, we hypothesize these indirect regulatory pathways include effects via APMK (e.g., see Panel 3G, 3H) and AKT (Panel 3D, 3E) have role(s) in the complexity of MuRF1's metabolic alterations observed in the cardiomyocytes.


 

Figure 4. Teaching points: This figure illustrates the regulation of an important metabolic kinase, AMPK by the ubiquitin ligase CHIP. CHIP acts as a chaperone for AMPK: In the presence of CHIP AMPK activity is regulated by phosphorylation at T172, however in the absence of CHIP AMPK is not activated by phosphorylation. Thus, CHIP is an essential part of downstream AMPK signaling, which includes increased lipid metabolism.

 


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David I. Brown, Traci L. Parry, Monte S. Willis. Ubiquitin Ligases and Posttranslational Regulation of Energy in the Heart: The Hand that Feeds. Compr Physiol 2017, 7: 841-862. doi: 10.1002/cphy.c160024