TY - JOUR
A1 - Wiedmer, Petra
A1 - Jung, Tobias
A1 - Castro, Jose Pedro
A1 - Pomatto, Laura C. D.
A1 - Sun, Patrick Y.
A1 - Davies, Kelvin J. A.
A1 - Grune, Tilman
T1 - Sarcopenia
BT - molecular mechanisms and open questions
JF - Ageing research reviews : ARR
N2 - Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality.
Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function.
In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and summarize the current view on molecular causes of sarcopenia development as well as open questions provoking further research efforts for establishing efficient lifestyle and therapeutic interventions.
KW - molecular pathways
KW - proteostasis
KW - proteasome
KW - autophagy
KW - mitochondria,
KW - muscle fibre composition
Y1 - 2020
U6 - https://doi.org/10.1016/j.arr.2020.101200
SN - 1568-1637
SN - 1872-9649
VL - 65
PB - Elsevier
CY - Clare
ER -
TY - JOUR
A1 - Korovila, Ioanna
A1 - Hoehn, Annika
A1 - Jung, Tobias
A1 - Grune, Tilman
A1 - Ott, Christiane
T1 - Reduced liver autophagy in high-fat diet induced liver steatosis in New Zealand obese mice
JF - Antioxidants : open access journal
N2 - Non-alcoholic fatty liver disease (NAFLD), as a consequence of overnutrition caused by high-calorie diets, results in obesity and disturbed lipid homeostasis leading to hepatic lipid droplet formation. Lipid droplets can impair hepatocellular function; therefore, it is of utmost importance to degrade these cellular structures. This requires the normal function of the autophagic-lysosomal system and the ubiquitin-proteasomal system. We demonstrated in NZO mice, a polygenic model of obesity, which were compared to C57BL/6J (B6) mice, that a high-fat diet leads to obesity and accumulation of lipid droplets in the liver. This was accompanied by a loss of autophagy efficiency whereas the activity of lysosomal proteases and the 20S proteasome remained unaffected. The disturbance of cellular protein homeostasis was further demonstrated by the accumulation of 3-nitrotyrosine and 4-hydroxynonenal modified proteins, which are normally prone to degradation. Therefore, we conclude that fat accumulation in the liver due to a high-fat diet is associated with a failure of autophagy and leads to the disturbance of proteostasis. This might further contribute to lipid droplet stabilization and accumulation.
KW - proteostasis
KW - protein modification
KW - 4-HNE
KW - proteasome
KW - lipid droplets
Y1 - 2021
U6 - https://doi.org/10.3390/antiox10040501
SN - 2076-3921
VL - 10
IS - 4
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Kuckelkorn, Ulrike
A1 - Stübler, Sabine
A1 - Textoris-Taube, Kathrin
A1 - Kilian, Christiane
A1 - Niewienda, Agathe
A1 - Henklein, Petra
A1 - Janek, Katharina
A1 - Stumpf, Michael P. H.
A1 - Mishto, Michele
A1 - Liepe, Juliane
T1 - Proteolytic dynamics of human 20S thymoproteasome
JF - The journal of biological chemistry
N2 - An efficient immunosurveillance of CD8(+) T cells in the periphery depends on positive/negative selection of thymocytes and thus on the dynamics of antigen degradation and epitope production by thymoproteasome and immunoproteasome in the thymus. Although studies in mouse systems have shown how thymoproteasome activity differs from that of immunoproteasome and strongly impacts the T cell repertoire, the proteolytic dynamics and the regulation of human thymoproteasome are unknown. By combining biochemical and computational modeling approaches, we show here that human 20S thymoproteasome and immunoproteasome differ not only in the proteolytic activity of the catalytic sites but also in the peptide transport. These differences impinge upon the quantity of peptide products rather than where the substrates are cleaved. The comparison of the two human 20S proteasome isoforms depicts different processing of antigens that are associated to tumors and autoimmune diseases.
KW - proteasome
KW - protein degradation
KW - antigen processing
KW - computational biology
KW - bioinformatics
KW - thymoproteasome
KW - thymus
KW - proteolysis
Y1 - 2019
U6 - https://doi.org/10.1074/jbc.RA118.007347
SN - 1083-351X
VL - 294
IS - 19
SP - 7740
EP - 7754
PB - American Society for Biochemistry and Molecular Biology
CY - Bethesda
ER -
TY - JOUR
A1 - Raupbach, Jana
A1 - Ott, Christiane
A1 - König, Jeannette
A1 - Grune, Tilman
T1 - Proteasomal degradation of glycated proteins depends on substrate unfolding: Preferred degradation of moderately modified myoglobin
JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2 - The Maillard reaction generates protein modifications which can accumulate during hyperglycemia or aging and may have inflammatory consequences. The proteasome is one of the major intracellular systems involved in the proteolytic degradation of modified proteins but its role in the degradation of glycated proteins is scarcely studied. In this study, chemical and structural changes of glycated myoglobin were analyzed and its degradation by 20S proteasome was studied. Myoglobin was incubated with physiological (5-10 mM), moderate (50-100 mM) and severe levels (300 mM) of glucose or methylglyoxal (MGO, 50 mM). Glycation increased myoglobin's fluorescence and surface hydrophobicity. Severe glycation generated crosslinked proteins as shown by gel electrophoresis. The concentration of advanced glycation endproducts (AGEs) N-epsilon-carboxymethyl lysine (CML), N-epsilon-carboxyethyl lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), pentosidine and pyrraline was analyzed after enzymatic hydrolysis followed by UPLC-MS/MS. Higher concentrations of glucose increased all analyzed AGEs and incubation with MGO led to a pronounced increase of CEL and MG-H1. The binding of the heme group to apo-myoglobin was decreased with increasing glycation indicating the loss of tertiary protein structure. Proteasomal degradation of modified myoglobin compared to native myoglobin depends on the degree of glycation: physiological conditions decreased proteasomal degradation whereas moderate glycation increased degradation. Severe glycation again decreased proteolytic cleavage which might be due to crosslinking of protein monomers. The activity of the proteasomal subunit beta 5 is influenced by the presence of glycated myoglobin. In conclusion, the role of the proteasome in the degradation of glycated proteins is highly dependent on the level of glycation and consequent protein unfolding.
KW - Glycation
KW - Myoglobin
KW - Heme
KW - Advanced glycation endproducts
KW - 20S
KW - proteasome
Y1 - 2020
U6 - https://doi.org/10.1016/j.freeradbiomed.2019.11.024
SN - 0891-5849
SN - 1873-4596
VL - 152
SP - 516
EP - 524
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Zaikin, Alexey
A1 - Kurths, Jürgen
T1 - Optimal length transportation hypothesis to model proteasome product size distribution
JF - Journal of biological physics : emphasizing physical principles in biological research ; an international journal for the formulation and application of mathematical models in the biological sciences
N2 - This paper discusses translocation features of the 20S proteasome in order to explain typical proteasome length distributions. We assume that the protein transport depends significantly on the fragment length with some optimal length which is transported most efficiently. By means of a simple one-channel model, we show that this hypothesis can explain both the one- and the three-peak length distributions found in experiments. A possible mechanism of such translocation is provided by so-called fluctuation-driven transport.
KW - proteasome
KW - protein translocation
KW - stochastic process
KW - ratchets
Y1 - 2006
U6 - https://doi.org/10.1007/s10867-006-9014-z
SN - 0092-0606
VL - 32
IS - 3-4
SP - 231
EP - 243
PB - Springer
CY - Dordrecht
ER -
TY - JOUR
A1 - Wendler, Petra
A1 - Enenkel, Cordula
T1 - Nuclear Transport of Yeast Proteasomes
JF - Frontiers in molecular biosciences
N2 - Proteasomes are key proteases in regulating protein homeostasis. Their holo-enzymes are composed of 40 different subunits which are arranged in a proteolytic core (CP) flanked by one to two regulatory particles (RP). Proteasomal proteolysis is essential for the degradation of proteins which control time-sensitive processes like cell cycle progression and stress response. In dividing yeast and human cells, proteasomes are primarily nuclear suggesting that proteasomal proteolysis is mainly required in the nucleus during cell proliferation. In yeast, which have a closed mitosis, proteasomes are imported into the nucleus as immature precursors via the classical import pathway. During quiescence, the reversible absence of proliferation induced by nutrient depletion or growth factor deprivation, proteasomes move from the nucleus into the cytoplasm. In the cytoplasm of quiescent yeast, proteasomes are dissociated into CP and RP and stored in membrane-less cytoplasmic foci, named proteasome storage granules (PSGs). With the resumption of growth, PSGs clear and mature proteasomes are transported into the nucleus by Blm10, a conserved 240 kDa protein and proteasome-intrinsic import receptor. How proteasomes are exported from the nucleus into the cytoplasm is unknown.
KW - proteasome
KW - nuclear transport
KW - importin
KW - karyopherin
KW - Blm10
KW - proteasome storage granules
Y1 - 2019
U6 - https://doi.org/10.3389/fmolb.2019.00034
SN - 2296-889X
VL - 6
PB - Frontiers Research Foundation
CY - Lausanne
ER -
TY - JOUR
A1 - Uestuen, Suayib
A1 - Börnke, Frederik
T1 - Interactions of Xanthomonas type-III effector proteins with the plant ubiquitin and ubiquitin-like pathways
JF - Frontiers in plant science
N2 - In eukaryotes, regulated protein turnover is required during many cellular processes, including defense against pathogens. Ubiquitination and degradation of ubiquitinated proteins via the ubiquitin proteasome system (UPS) is the main pathway for the turnover of intracellular proteins in eukaryotes. The extensive utilization of the UPS in host cells makes it an ideal pivot for the manipulation of cellular processes by pathogens. Like many other Gram-negative bacteria, Xanthomonas species secrete a suite of type-III effector proteins (T3Es) into their host cells to promote virulence. Some of these T3Es exploit the plant UPS to interfere with immunity. This review summarizes T3E examples from the genus Xanthomonas with a proven or suggested interaction with the host UPS or UPS-like systems and also discusses the apparent paradox that arises from the presence of T3Es that inhibit the UPS in general while others rely on its activity for their function.
KW - Xanthomonas
KW - type-III effector
KW - ubiquitin
KW - proteasome
KW - plant defense
Y1 - 2014
U6 - https://doi.org/10.3389/fpls.2014.00736
SN - 1664-462X
VL - 5
PB - Frontiers Research Foundation
CY - Lausanne
ER -
TY - JOUR
A1 - Nguyen, Hung M.
A1 - Schippers, Jos H. M.
A1 - Goni-Ramos, Oscar
A1 - Christoph, Mathias P.
A1 - Dortay, Hakan
A1 - van der Hoorn, Renier A. L.
A1 - Müller-Röber, Bernd
T1 - An upstream regulator of the 26S proteasome modulates organ size in Arabidopsis thaliana
JF - The plant journal
N2 - In both animal and plant kingdoms, body size is a fundamental but still poorly understood attribute of biological systems. Here we report that the Arabidopsis NAC transcription factor Regulator of Proteasomal Gene Expression' (RPX) controls leaf size by positively modulating proteasome activity. We further show that the cis-element recognized by RPX is evolutionarily conserved between higher plant species. Upon over-expression of RPX, plants exhibit reduced growth, which may be reversed by a low concentration of the pharmacological proteasome inhibitor MG132. These data suggest that the rate of protein turnover during growth is a critical parameter for determining final organ size.
KW - Arabidopsis thaliana
KW - organ size
KW - evolution
KW - leaf development
KW - proteasome
KW - gene regulatory network
Y1 - 2013
U6 - https://doi.org/10.1111/tpj.12097
SN - 0960-7412
VL - 74
IS - 1
SP - 25
EP - 36
PB - Wiley-Blackwell
CY - Hoboken
ER -