Intracellular Protein Degradation: From a Vague Idea through the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting

Ciechanover, Aaron

doi:10.1159/000334283

Cited by 76 publications

(67 citation statements)

References 130 publications

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“…The proteasome is a tubular protein degradation system for misfolded or damaged intracellular proteins, particularly those marked for degradation by polyubiquitination, which are proteolytically cleaved by the caspase, chymotrypsin, and trypsin-like activities [24]. The proteasome mutations decrease the proteolytic activities [12–14] and might impair adipocyte differentiation based on PSMB8 knockdown experiments [14].…”

Section: Clinical and Pathogenic Description Of The Mendelian (Monogementioning

confidence: 99%

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

2016

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Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of “autoinflammatory” and “autoimmune” interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.

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Section: Clinical and Pathogenic Description Of The Mendelian (Monogementioning

confidence: 99%

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

2016

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“…Their emphasis has been on a bottom up approach, finding associations in mRNA and protein profiles, the transcriptome and the proteome, in order to define the pathways for synthesis, proteolysis, and regulation of fluxes. But proteolysis, or autophagy, cleaning out old proteins and recycling their amino acids, is just as important as manufacturing proteins 41 [Ciechanover, 2012]. Generalized autophagy is stimulated by exercise 60 [He 2012] and is probably one of the reasons that exercise regimens prolong life.…”

Section: Section VI Tracking the Relationships From Organ To Genomementioning

confidence: 99%

Modeling to Link Regional Myocardial Work, Metabolism and Blood Flows

et al. 2012

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Given the mono-functional, highly coordinated processes of cardiac excitation and contraction, the observations that regional myocardial blood flows, rMBF, are broadly heterogeneous has provoked much attention, but a clear explanation has not emerged. In isolated and in vivo heart studies the total coronary flow is found to be proportional to the rate-pressure product (systolic mean blood pressure times heart rate), a measure of external cardiac work. The same relationship might be expected on a local basis: more work requires more flow. The validity of this expectation has never been demonstrated experimentally. In this article we review the concepts linking cellular excitation and contractile work to cellular energetics and ATP demand, substrate utilization, oxygen demand, vasoregulation, and local blood flow. Mathematical models of these processes are now rather well developed. We propose that the construction of an integrated model encompassing the biophysics, biochemistry and physiology of cardiomyocyte contraction, then combined with a detailed three-dimensional structuring of the fiber bundle and sheet arrangements of the heart as a whole will frame an hypothesis that can be quantitatively evaluated to settle the prime issue: Does local work drive local flow in a predictable fashion that explains the heterogeneity? While in one sense one can feel content that work drives flow is irrefutable, there are no cardiac contractile models that demonstrate the required heterogeneity in local strain-stress-work; quite the contrary, cardiac contraction models have tended toward trying to show that work should be uniform. The object of this review is to argue that uniformity of work does not occur, and is impossible in any case, and that further experimentation and analysis are necessary to test the hypothesis.

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“…As mentioned above, the proteasome is enriched in the nucleus [35], supporting the idea that ubiquitin-mediated proteasomal degradation is a primary route for misfolded protein elimination in the nucleus. The small signaling protein ubiquitin is covalently attached to target substrates via a conserved enzymatic cascade [96]. Initially, a ubiquitin-activating enzyme, or E1, binds ubiquitin in a high-energy thiol-ester bond.…”

Section: Nuclear Pqc – Ubiquitin-protein Ligasesmentioning

confidence: 99%

Cellular maintenance of nuclear protein homeostasis

Oeser

Abraham

Kaganovich

et al. 2013

Cell. Mol. Life Sci.

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The accumulation and aggregation of misfolded proteins is the primary hallmark for more than 45 human degenerative diseases. These devastating disorders include Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS). Over 15 degenerative diseases are associated with the aggregation of misfolded proteins specifically in the nucleus of cells. But, how the cell safeguards the nucleus from misfolded proteins is not entirely clear. In this review, we discuss what is currently known about the cellular mechanisms that maintain protein homeostasis in the nucleus and protect the nucleus from misfolded protein accumulation and aggregation. In particular, we focus on the chaperones found to localize to the nucleus during stress, the ubiquitin-proteasome components enriched in the nucleus, the signaling systems that might be present in the nucleus to coordinate folding and degradation, and the sites of misfolded protein deposition associated with the nucleus.

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Intracellular Protein Degradation: From a Vague Idea through the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting

Cited by 76 publications

References 130 publications

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus

Modeling to Link Regional Myocardial Work, Metabolism and Blood Flows

Cellular maintenance of nuclear protein homeostasis

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