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Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling

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ABSTRACT

Ubiquitin (UB) is a highly conserved low molecular weight (8.5 kDa) protein. It consists of 76 amino acid residues and is found in all eukaryotic cells. The covalent linkage of UB to a variety of cellular proteins (ubiquitination) is one of the most common posttranslational modifications in eukaryotic cells. This modification generally regulates protein turnover and protects the cells from damaged or misfolded proteins. The polyubiquitination of proteins serves as a signal for degradation via the 26S proteasome pathway. UB is present in trace amounts in body fluids. Elevated levels of UB are described in the serum or plasma of patients under a variety of conditions. Extracellular UB is proposed to have pleiotropic roles including regulation of immune response, anti‐inflammatory, and neuroprotective activities. CXCR4 is identified as receptor for extracellular UB in hematopoietic cells. Heart failure represents a major cause of morbidity and mortality in western society. Cardiac remodeling is a determinant of the clinical course of heart failure. The components involved in myocardial remodeling include—myocytes, fibroblasts, interstitium, and coronary vasculature. Increased sympathetic nerve activity in the form of norepinephrine is a common feature during heart failure. Acting via β‐adrenergic receptor (β‐AR), norepinephrine is shown to induce myocyte apoptosis and myocardial fibrosis. β‐AR stimulation increases extracellular levels of UB in myocytes, and UB inhibits β‐AR‐stimulated increases in myocyte apoptosis and myocardial fibrosis. This review summarizes intracellular and extracellular functions of UB with particular emphasis on the role of extracellular UB in cardiac myocyte apoptosis and myocardial remodeling. © 2016 American Physiological Society. Compr Physiol 6:527‐560, 2016.

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Figure 1. Figure 1. A ribbon diagram of UB. The dark orange segment (black arrow) of the orange β‐sheet indicates the N‐terminus of UB. The yellow, orange and purple planes indicate the mixed β‐sheet, lime green indicates the large α‐helix. The hydrophobic surface patch residues surrounding Ile‐44, common interaction residues are indicated by red sticks and labeled accordingly. Light blue Asp‐58 indicates a hydrophilic binding area, pink Phe‐4 indicates a hydrophobic interaction site and the forest green C‐terminus indicates the flexible di‐glycine residues. [Vijay‐Kumar et al., PDB File: 1UBQ, Ref. Accelrys Software Inc., Discovery Studio Visualizer, Release 4.0, San Diego: Accelrys Software Inc., 2013].
Figure 2. Figure 2. The complete amino acid sequence for human UB. Important hydrophobic residue is in pink, hydrophilic binding area is in light blue, amino acid residues of hydrophobic patch are in red and lysine residues available for polyubiquitination are shown in green.
Figure 3. Figure 3. Representative diagram of the UB‐proteasome pathway first proposed by Hershko et al. At the time (1980), UB had not yet been identified and was referred to as APF‐1 (green circles). The diagram demonstrates ATP‐dependent polyubiquitination in step 1. Step 2 incorporates what we now know to the proteasome but was initially referred to as “peptidases” which break the protein down into amino acids (blue circles). Step 3 shows the cleavage of polyUB from the protein into free ubiquitin, which then becomes available for binding to another protein, tagging it for degradation as well. [Adapted from Hershko et al. 1980 ()].
Figure 4. Figure 4. Simplified schematic representation of UB‐proteasome pathway. UB (black circle) becomes activated (green circle) by E1 UB activating protein and ATP (step 1). Activated UB is then transferred to E2 UB carrier protein (step 2) where it is carried and transferred to E3 UB ligase (step 3). The E3 ligase covalently binds the UB to a lysine residue (step 4) on the target protein (pink). This process continues (steps 5‐8) until four or more UB molecules are bound to the protein of interest at which point the 26S proteasome recognizes the polyUB tagged protein (step 9) for degradation utilizing ATP.
Figure 5. Figure 5. A ribbon diagram of chemokine C‐X‐C motif receptor 4 (CXCR4) with seven differently colored transmembrane helices. The ECLs are at the top of the figure, the intracellular loops are at the bottom, and the helices reside within the lipid bilayer. The proposed UB‐CXCR4 interaction sites are displayed in blue, with labels. ECL2 and ECL3 denote ECLs of CXCR4 that are thought to be critical for UB binding. [Wu B et al., PDB File: 3ODU, Ref. Accelrys Software Inc., Discovery Studio Visualizer, Release 4.0, San Diego: Accelrys Software Inc., 2013.]
Figure 6. Figure 6. Ribbon diagram of UB interacting with CXCR4 with adjusted docking based on charge complementarity and mutational data. UB is blue and CXCR4 is pink. Sites believed to be critical binding components are labeled with their amino acid one letter code and location. “E” denotes ECLs and “I” denotes intracellular loops. [From Saini et al. 2011 () with permission.]
Figure 7. Figure 7. Flow diagram displaying three pathways of apoptosis. (A) Intrinsic pathway triggered by nutrient deprivation or cellular stress increases expression of BH3‐only proteins including BID, BAD and BIM which contribute to mitochondrial damage by means of BAK‐BAX oligomeric channels. Antiapoptotic Bcl‐2 proteins can interact with the BH3‐only proteins to inhibit mitochondrial channel formation. BAK‐BAX oligomeric channels cause cytochrome c (yellow circles) to leak from the mitochondria into the cytosol triggering formation of apoptotsomes and activation of caspase‐9. (B) Extrinsic or receptor‐mediated pathway involves death signal TNF‐α or FasL binding to the death receptor, leading to its interaction with FADD and activating caspase‐8 (represented by the scissor opening). Active caspase‐8 may cleave BID to tBid, which contributes to channel formation in the mitochondria, causing leakage of cytochrome c. Caspase‐8 can also directly activate caspase‐7 and caspase‐3. (C) Granzyme pathway initiates apoptosis via the activation of caspase‐3, which can then activate other caspases. The granzyme B pathway can also act via BID cleavage.
Figure 8. Figure 8. Proteome map depicting identification of UB in the conditioned media of ARVMs. ARVMs, plated for 24 h, were treated with ISO (10 μmol/L) for 3 h. Conditioned media were analyzed by two‐dimensional gel electrophoresis. The gels were stained with SYPRO Ruby fluorescent protein stain. The circled protein was analyzed by MALDI‐TOF MS/MS and identified as UB. [From Singh et al. (). Extracellular UB inhibits β‐AR‐stimulated apoptosis in cardiac myocytes: role of GSK‐3β and mitochondrial pathways. Cardiovascular Research, 2010, 86(1): 20‐28, by permission of Oxford University Press.]
Figure 9. Figure 9. UB treatment inhibits β‐AR‐stimulated apoptosis in ARVMs. ARVMs, plated for 24 h, were pretreated with UB (10 μg/mL) for 30 min followed by treatment with ISO (10 μmol/L; UB+ISO) or pretreated with ISO (10 μmol/L) for 30 min followed by treatment with UB (10 μg/mL; ISO + UB). Measurement of apoptosis using TUNEL‐assay indicated that pretreatment with UB inhibits β‐AR‐stimulated apoptosis. The antiapoptotic effects of UB were preserved even when the cells were treated with UB 30 min after β‐AR stimulation. CTL, control; *P < 0.05 versus CTL; #P < 0.05 versus ISO. [From Singh et al., (). Extracellular ubiquitin inhibits β‐AR‐stimulated apoptosis in cardiac myocytes: role of GSK‐3β and mitochondrial pathways. Cardiovascular Research, 2010, 86(1): 20‐28, by permission of Oxford University Press.]
Figure 10. Figure 10. Exogenous UB decreases β‐AR‐stimulated apoptosis in the heart. β‐AR agonist ISO (7 days) infusion increases the percentage of apoptotic myocyte. Exogenous UB in the presence of ISO (ISO + UB) significantly decreased the percentage of apoptotic myocytes. UB infusion alone had no effect on apoptosis. *P < 0.05 versus sham; #P < 0.05 versus ISO [From Daniels et al. 2012 () with permission.]
Figure 11. Figure 11. Summary diagram illustrating the potential pathway for UB in β‐AR‐stimulated myocardial remodeling. β1‐AR stimulated interaction with Gαs increases cAMP levels and activates PKA, leading to activation of JNKs, GSK‐3β, CAMKII, and mitochondrial death pathway of apoptosis. β‐AR stimulation also increases extracellular levels of UB. Extracellular UB can then stimulate intracellular signaling via its interaction with CXCR4 (a potential receptor in cardiac cells). UB‐mediated intracellular signaling may then play an antiapoptotic and antifibrotic roles via the activation of PI3‐kinase/Akt pathway. UB may also influence the remodeling process of the heart by acting as a proangiogenic factor.
Figure 12. Figure 12. Exogenous UB inhibits β‐AR‐stimulated myocardial fibrosis. Heart sections were stained with Masson's trichrome staining to distinguish muscle tissue (red) from fibrosis (blue). ISO infusion (7 days) increases myocardial fibrosis. Exogenous UB in the presence of ISO (ISO + UB) decreases myocardial fibrosis. UB infusion alone had no effect on myocardial fibrosis. [From Daniels et al. 2012 () with permission.]
Figure 13. Figure 13. Treatment with UB promotes angiogenesis in CMECs. Matrigel assay demonstrating angiogenic potential of UB (20 μg/mL), methylated UB (unable to form polyUB chains; 20 μg/mL), fetal bovine serum (FBS; 20%), and SDF‐1α (CXCL12; 1 nM). AMD3100 (CXCR4 antagonist; 100 μmol/L) pretreatment negated the proangiogenic effect of UB. Panel A depicts 10× magnification of tubular structures, whereas panel B depicts 20× magnification. Black arrows indicate tubule sprouting. Panel C depicts quantitation of the percent area occupied by the tubular structure. [From Steagall et al. (). Microcirculation. Extracellular ubiquitin increases expression of angiogenic molecules and stimulates angiogenesis in CMECs, 21(4): 324‐332, doi: 10.1111/micc.12109, with permission.]


Figure 1. A ribbon diagram of UB. The dark orange segment (black arrow) of the orange β‐sheet indicates the N‐terminus of UB. The yellow, orange and purple planes indicate the mixed β‐sheet, lime green indicates the large α‐helix. The hydrophobic surface patch residues surrounding Ile‐44, common interaction residues are indicated by red sticks and labeled accordingly. Light blue Asp‐58 indicates a hydrophilic binding area, pink Phe‐4 indicates a hydrophobic interaction site and the forest green C‐terminus indicates the flexible di‐glycine residues. [Vijay‐Kumar et al., PDB File: 1UBQ, Ref. Accelrys Software Inc., Discovery Studio Visualizer, Release 4.0, San Diego: Accelrys Software Inc., 2013].


Figure 2. The complete amino acid sequence for human UB. Important hydrophobic residue is in pink, hydrophilic binding area is in light blue, amino acid residues of hydrophobic patch are in red and lysine residues available for polyubiquitination are shown in green.


Figure 3. Representative diagram of the UB‐proteasome pathway first proposed by Hershko et al. At the time (1980), UB had not yet been identified and was referred to as APF‐1 (green circles). The diagram demonstrates ATP‐dependent polyubiquitination in step 1. Step 2 incorporates what we now know to the proteasome but was initially referred to as “peptidases” which break the protein down into amino acids (blue circles). Step 3 shows the cleavage of polyUB from the protein into free ubiquitin, which then becomes available for binding to another protein, tagging it for degradation as well. [Adapted from Hershko et al. 1980 ()].


Figure 4. Simplified schematic representation of UB‐proteasome pathway. UB (black circle) becomes activated (green circle) by E1 UB activating protein and ATP (step 1). Activated UB is then transferred to E2 UB carrier protein (step 2) where it is carried and transferred to E3 UB ligase (step 3). The E3 ligase covalently binds the UB to a lysine residue (step 4) on the target protein (pink). This process continues (steps 5‐8) until four or more UB molecules are bound to the protein of interest at which point the 26S proteasome recognizes the polyUB tagged protein (step 9) for degradation utilizing ATP.


Figure 5. A ribbon diagram of chemokine C‐X‐C motif receptor 4 (CXCR4) with seven differently colored transmembrane helices. The ECLs are at the top of the figure, the intracellular loops are at the bottom, and the helices reside within the lipid bilayer. The proposed UB‐CXCR4 interaction sites are displayed in blue, with labels. ECL2 and ECL3 denote ECLs of CXCR4 that are thought to be critical for UB binding. [Wu B et al., PDB File: 3ODU, Ref. Accelrys Software Inc., Discovery Studio Visualizer, Release 4.0, San Diego: Accelrys Software Inc., 2013.]


Figure 6. Ribbon diagram of UB interacting with CXCR4 with adjusted docking based on charge complementarity and mutational data. UB is blue and CXCR4 is pink. Sites believed to be critical binding components are labeled with their amino acid one letter code and location. “E” denotes ECLs and “I” denotes intracellular loops. [From Saini et al. 2011 () with permission.]


Figure 7. Flow diagram displaying three pathways of apoptosis. (A) Intrinsic pathway triggered by nutrient deprivation or cellular stress increases expression of BH3‐only proteins including BID, BAD and BIM which contribute to mitochondrial damage by means of BAK‐BAX oligomeric channels. Antiapoptotic Bcl‐2 proteins can interact with the BH3‐only proteins to inhibit mitochondrial channel formation. BAK‐BAX oligomeric channels cause cytochrome c (yellow circles) to leak from the mitochondria into the cytosol triggering formation of apoptotsomes and activation of caspase‐9. (B) Extrinsic or receptor‐mediated pathway involves death signal TNF‐α or FasL binding to the death receptor, leading to its interaction with FADD and activating caspase‐8 (represented by the scissor opening). Active caspase‐8 may cleave BID to tBid, which contributes to channel formation in the mitochondria, causing leakage of cytochrome c. Caspase‐8 can also directly activate caspase‐7 and caspase‐3. (C) Granzyme pathway initiates apoptosis via the activation of caspase‐3, which can then activate other caspases. The granzyme B pathway can also act via BID cleavage.


Figure 8. Proteome map depicting identification of UB in the conditioned media of ARVMs. ARVMs, plated for 24 h, were treated with ISO (10 μmol/L) for 3 h. Conditioned media were analyzed by two‐dimensional gel electrophoresis. The gels were stained with SYPRO Ruby fluorescent protein stain. The circled protein was analyzed by MALDI‐TOF MS/MS and identified as UB. [From Singh et al. (). Extracellular UB inhibits β‐AR‐stimulated apoptosis in cardiac myocytes: role of GSK‐3β and mitochondrial pathways. Cardiovascular Research, 2010, 86(1): 20‐28, by permission of Oxford University Press.]


Figure 9. UB treatment inhibits β‐AR‐stimulated apoptosis in ARVMs. ARVMs, plated for 24 h, were pretreated with UB (10 μg/mL) for 30 min followed by treatment with ISO (10 μmol/L; UB+ISO) or pretreated with ISO (10 μmol/L) for 30 min followed by treatment with UB (10 μg/mL; ISO + UB). Measurement of apoptosis using TUNEL‐assay indicated that pretreatment with UB inhibits β‐AR‐stimulated apoptosis. The antiapoptotic effects of UB were preserved even when the cells were treated with UB 30 min after β‐AR stimulation. CTL, control; *P < 0.05 versus CTL; #P < 0.05 versus ISO. [From Singh et al., (). Extracellular ubiquitin inhibits β‐AR‐stimulated apoptosis in cardiac myocytes: role of GSK‐3β and mitochondrial pathways. Cardiovascular Research, 2010, 86(1): 20‐28, by permission of Oxford University Press.]


Figure 10. Exogenous UB decreases β‐AR‐stimulated apoptosis in the heart. β‐AR agonist ISO (7 days) infusion increases the percentage of apoptotic myocyte. Exogenous UB in the presence of ISO (ISO + UB) significantly decreased the percentage of apoptotic myocytes. UB infusion alone had no effect on apoptosis. *P < 0.05 versus sham; #P < 0.05 versus ISO [From Daniels et al. 2012 () with permission.]


Figure 11. Summary diagram illustrating the potential pathway for UB in β‐AR‐stimulated myocardial remodeling. β1‐AR stimulated interaction with Gαs increases cAMP levels and activates PKA, leading to activation of JNKs, GSK‐3β, CAMKII, and mitochondrial death pathway of apoptosis. β‐AR stimulation also increases extracellular levels of UB. Extracellular UB can then stimulate intracellular signaling via its interaction with CXCR4 (a potential receptor in cardiac cells). UB‐mediated intracellular signaling may then play an antiapoptotic and antifibrotic roles via the activation of PI3‐kinase/Akt pathway. UB may also influence the remodeling process of the heart by acting as a proangiogenic factor.


Figure 12. Exogenous UB inhibits β‐AR‐stimulated myocardial fibrosis. Heart sections were stained with Masson's trichrome staining to distinguish muscle tissue (red) from fibrosis (blue). ISO infusion (7 days) increases myocardial fibrosis. Exogenous UB in the presence of ISO (ISO + UB) decreases myocardial fibrosis. UB infusion alone had no effect on myocardial fibrosis. [From Daniels et al. 2012 () with permission.]


Figure 13. Treatment with UB promotes angiogenesis in CMECs. Matrigel assay demonstrating angiogenic potential of UB (20 μg/mL), methylated UB (unable to form polyUB chains; 20 μg/mL), fetal bovine serum (FBS; 20%), and SDF‐1α (CXCL12; 1 nM). AMD3100 (CXCR4 antagonist; 100 μmol/L) pretreatment negated the proangiogenic effect of UB. Panel A depicts 10× magnification of tubular structures, whereas panel B depicts 20× magnification. Black arrows indicate tubule sprouting. Panel C depicts quantitation of the percent area occupied by the tubular structure. [From Steagall et al. (). Microcirculation. Extracellular ubiquitin increases expression of angiogenic molecules and stimulates angiogenesis in CMECs, 21(4): 324‐332, doi: 10.1111/micc.12109, with permission.]
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Stephanie L.C. Scofield, Parthiv Amin, Mahipal Singh, Krishna Singh. Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling. Compr Physiol 2015, 6: 527-560. doi: 10.1002/cphy.c150025