The ATP Costs and Time Required to Degrade Ubiquitinated Proteins by the 26 S Proteasome

Peth, Andreas; Nathan, James A.; Goldberg, Alfred L.

doi:10.1074/jbc.m113.482570

Cited by 125 publications

(135 citation statements)

References 33 publications

(78 reference statements)

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“…34 In our model, the inability of brain to handle oxidized/damaged proteins by the proteasome system was manifested as an accumulation of Ub-Pr ( Figure 5B). The LEH infusion resulted in a significant reduction in Ub-Pr expression, indicating the salutary effect of improved ATP content caused by LEH.…”

Section: Discussionmentioning

confidence: 80%

The Brain Metabolic Activity after Resuscitation with Liposome-Encapsulated Hemoglobin in a Rat Model of Hypovolemic Shock

Rao

Hedrick

Yadav

et al. 2015

J Cereb Blood Flow Metab

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We examined the effect of resuscitation with liposome-encapsulated hemoglobin (LEH) on cerebral bioenergetics in a rat model of 45% hypovolemia. The rats were resuscitated with isovolemic LEH or saline after 15 minutes of shock and followed up to 6 hours. Untreated hypovolemic rats received no fluid. The cerebral uptake of F-18-fluorodeoxyglucose (FDG) was measured by PET, and at 6 hours, the brain was collected for various assays. Hypovolemia decreased cellular adenosine triphosphate (ATP), phosphocreatine, nicotinamide adenine dinucleotide (NAD)/NADH ratio, citrate synthase activity, glucose-6-phosphate, and nerve growth factor (NGF), even when FDG uptake remained unchanged. The FDG uptake was reduced by saline, but not by LEH infusion. The reduced FDG uptake in saline group was associated with a decrease in hexokinase I expression. The LEH infusion effectively restored ATP content, NAD/NADH ratio, and NGF expression, and reduced the hypovolemia-induced accumulation of pyruvate and ubiquitinated proteins; in comparison, saline was significantly less effective. The LEH infusion was associated with low pH and high anion gap, indicating anionic gap acidosis. The results suggest that hypovolemic shock perturbs glucose metabolism at the level of pyruvate utilization, resulting in deranged cerebral energy stores. The correction of volume and oxygen deficits by LEH recovers the cerebral metabolism and creates a prosurvival phenotype.

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Section: Discussionmentioning

confidence: 80%

The Brain Metabolic Activity after Resuscitation with Liposome-Encapsulated Hemoglobin in a Rat Model of Hypovolemic Shock

Rao

Hedrick

Yadav

et al. 2015

J Cereb Blood Flow Metab

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“…Protein degradation cost was based on 1 to 1.5 ATP per residue in the proteasome degradation pathway (Peth et al, 2013). Protein synthesis cost was based on 5 to 5.5 ATP per residue in ribosome translation, protein transport and amino acid biosynthesis (Piques et al, 2009;Kaleta et al, 2013).…”

Section: Energy Cost and Production For Protein Turnovermentioning

confidence: 99%

Protein Degradation Rate in Arabidopsis thaliana Leaf Growth and Development

et al. 2017

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We applied 15 N labeling approaches to leaves of the Arabidopsis thaliana rosette to characterize their protein degradation rate and understand its determinants. The progressive labeling of new peptides with 15 N and measuring the decrease in the abundance of >60,000 existing peptides over time allowed us to define the degradation rate of 1228 proteins in vivo. We show that Arabidopsis protein half-lives vary from several hours to several months based on the exponential constant of the decay rate for each protein. This rate was calculated from the relative isotope abundance of each peptide and the fold change in protein abundance during growth. Protein complex membership and specific protein domains were found to be strong predictors of degradation rate, while N-end amino acid, hydrophobicity, or aggregation propensity of proteins were not. We discovered rapidly degrading subunits in a variety of protein complexes in plastids and identified the set of plant proteins whose degradation rate changed in different leaves of the rosette and correlated with leaf growth rate. From this information, we have calculated the protein turnover energy costs in different leaves and their key determinants within the proteome.

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“…The rates of degradation of ubiquitinated protein by the proteasomes are proportional to their rate of ATP hydrolysis and several steps in the degradation of ubiquitinated proteins by 26S proteasomes are coupled to ATP hydrolysis (4,34,35). We therefore assayed whether raising cAMP affected the proteasome's ability to hydrolyze ATP.…”

Section: Proteasome Phosphorylation Enhances Its Capacity To Hydrolyzementioning

confidence: 99%

“…3A (Left), 26S purified from rolipram-treated myotubes had higher ATPase activity than those from untreated cells. ATP hydrolysis by proteasomes is stimulated about twofold by Ub conjugates, or by a combination of a loosely folded protein (e.g., casein) and a free Ub chain (34). The addition of hexa-Ub (Ub 6 ) chains together with casein stimulated similarly the ATPase activity of particles from control and rolipram-treated cells.…”

Section: Proteasome Phosphorylation Enhances Its Capacity To Hydrolyzementioning

confidence: 99%

cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins

Lokireddy

Kukushkin

Goldberg

2015

Proc. Natl. Acad. Sci. U.S.A.

195

255

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Although rates of protein degradation by the ubiquitin-proteasome pathway (UPS) are determined by their rates of ubiquitination, we show here that the proteasome's capacity to degrade ubiquitinated proteins is also tightly regulated. We studied the effects of cAMPdependent protein kinase (PKA) on proteolysis by the UPS in several mammalian cell lines. Various agents that raise intracellular cAMP and activate PKA (activators of adenylate cyclase or inhibitors of phosphodiesterase 4) promoted degradation of short-lived (but not long-lived) cell proteins generally, model UPS substrates having different degrons, and aggregation-prone proteins associated with major neurodegenerative diseases, including mutant FUS (Fused in sarcoma), SOD1 (superoxide dismutase 1), TDP43 (TAR DNA-binding protein 43), and tau. 26S proteasomes purified from these treated cells or from control cells and treated with PKA degraded ubiquitinated proteins, small peptides, and ATP more rapidly than controls, but not when treated with protein phosphatase. Raising cAMP levels also increased amounts of doubly capped 26S proteasomes. Activated PKA phosphorylates the 19S subunit, Rpn6/PSMD11 (regulatory particle non-ATPase 6/proteasome subunit D11) at Ser14. Overexpression of a phosphomimetic Rpn6 mutant activated proteasomes similarly, whereas a nonphosphorylatable mutant decreased activity. Thus, proteasome function and protein degradation are regulated by cAMP through PKA and Rpn6, and activation of proteasomes by this mechanism may be useful in treating proteotoxic diseases.protein degradation | proteasomes | cAMP | cAMP-dependent protein kinase | Rpn6/PSMD11

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The ATP Costs and Time Required to Degrade Ubiquitinated Proteins by the 26 S Proteasome

Cited by 125 publications

References 33 publications

The Brain Metabolic Activity after Resuscitation with Liposome-Encapsulated Hemoglobin in a Rat Model of Hypovolemic Shock

The Brain Metabolic Activity after Resuscitation with Liposome-Encapsulated Hemoglobin in a Rat Model of Hypovolemic Shock

Protein Degradation Rate in Arabidopsis thaliana Leaf Growth and Development

cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins

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