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Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection.

ABSTRACT: Post-translational modification represents an important mechanism to regulate protein function in cardiac cells. Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are a family of protein modifiers that share a certain extent of sequence and structure similarity. Conjugation of Ub or UBLs to target proteins is dynamically regulated by a set of UBL-specific enzymes and modulates the physical and physiological properties of protein substrates. Ub and UBLs control a strikingly wide spectrum of cellular processes and not surprisingly are involved in the development of multiple human diseases including cardiac diseases. Further identification of novel UBL targets will expand our understanding of the functional diversity of UBL pathways in physiology and pathology. Here we review recent findings on the mechanisms, proteome and functions of a subset of UBLs and highlight their potential impacts on the development and progression of various forms of cardiac diseases.

SUBMITTER: Li J

PROVIDER: S-EPMC4899309 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection.

Li Jie J Johnson John A JA Su Huabo H

Current drug targets 20180101 9

Post-translational modification represents an important mechanism to regulate protein function in cardiac cells. Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are a family of protein modifiers that share a certain extent of sequence and structure similarity. Conjugation of Ub or UBLs to target proteins is dynamically regulated by a set of UBL-specific enzymes and modulates the physical and physiological properties of protein substrates. Ub and UBLs control a strikingly wide spectrum of cellu ...[more]

PMID: 26648080

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Project description:BackgroundIncreasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates.MethodsProteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68).ResultsA pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD.ConclusionIn summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD.

Project description:SDF-1? (stromal cell-derived factor-1?) is a CXCR4-receptor agonist and DPP4 (dipeptidyl peptidase 4) substrate. SDF-1?, particularly when combined with sitagliptin to block the metabolism of SDF-1? by DPP4, stimulates proliferation of cardiac fibroblasts via the CXCR4 receptor; this effect is greater in cells from spontaneously hypertensive rats versus Wistar-Kyoto normotensive rats. Emerging evidence indicates that ubiquitin(1-76) exists in plasma and is a potent CXCR4-receptor agonist. Therefore, we hypothesized that ubiquitin(1-76), similar to SDF-1?, should increase proliferation of cardiac fibroblasts. Contrary to our working hypothesis, ubiquitin(1-76) did not stimulate cardiac fibroblast proliferation, yet unexpectedly antagonized the proproliferative effects of SDF-1? combined with sitagliptin. In this regard, ubiquitin(1-76) was more potent in spontaneously hypertensive versus Wistar-Kyoto cells. In the presence of 6bk (selective inhibitor of insulin-degrading enzyme [IDE]; an enzyme known to convert ubiquitin(1-76) to ubiquitin(1-74)), ubiquitin(1-76) no longer antagonized the proproliferative effects of SDF-1?/sitagliptin. Ubiquitin(1-74) also antagonized the proproliferative effects of SDF-1?/sitagliptin, and this effect of ubiquitin(1-74) was not blocked by 6bk and was >10-fold more potent compared with ubiquitin(1-76). Neither ubiquitin(1-76) nor ubiquitin(1-74) inhibited the proproliferative effects of the non-CXCR4 receptor agonist neuropeptide Y (activates Y1 receptors). Cardiac fibroblasts expressed IDE mRNA, protein, and activity and converted ubiquitin(1-76) to ubiquitin(1-74). Spontaneously hypertensive fibroblasts expressed greater IDE activity. Extracellular ubiquitin(1-76) blocks the proproliferative effects of SDF-1?/sitagliptin via its conversion by IDE to ubiquitin(1-74), a potent CXCR4 antagonist. Thus, IDE inhibitors, particularly when combined with DPP4 inhibitors or hypertension, could increase the risk of cardiac fibrosis.

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Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection.

Publications

Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection.

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