Proteasome Endopeptidase Complex

Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

The burden of protein misfolding is believed to contribute to aging. However, the links between adaptations to conditions associated with protein misfolding and resistance to the time-dependent attrition of cellular function remain poorly understood. We report that worms lacking aip-1, a homologue of mammalian AIRAP (arsenic-inducible proteasomal 19S regulatory particle-associated protein), are not only impaired in their ability to resist exposure to arsenite but also exhibit shortened lifespan and hypersensitivity to misfolding-prone proteins under normal laboratory conditions.

Author(s): 
Yun, Chi
Stanhill, Ariel
Yang, Yun
Zhang, Yuhong
Haynes, Cole M.
Xu, Chong-Feng
Neubert, Thomas A.
Mor, Adam
Philips, Mark R.
Ron, David
Publication Title: 
Aging Cell

Proteasome-dependent degradation has been extensively investigated and has been shown to play a vital role in the maintenance of cellular homeostasis. Proteasome activity and expression are reduced during aging and replicative senescence. Its activation has been shown to confer lifespan extension in human diploid fibroblasts (HDFs), whereas partial proteasome inhibition triggers an irreversible premature senescent state in young HDFs.

Author(s): 
Chondrogianni, Niki
Trougakos, Ioannis P.
Kletsas, Dimitris
Chen, Qin M.
Gonos, Efstathios S.
Publication Title: 
The Journal of Biological Chemistry

Replicative senescence in human fibroblasts is accompanied with alterations of various biological processes, including the impaired function of the proteasome. The proteasome is responsible for the removal of both normal and damaged proteins. Due to its latter function, proteasome is also considered a representative secondary antioxidant cellular mechanism. Nrf2 is a basic transcription factor responsible for the regulation of the cellular antioxidant response that has also been shown to regulate several proteasome subunits in mice.

Author(s): 
Kapeta, Suzanne
Chondrogianni, Niki
Gonos, Efstathios S.
Publication Title: 
Experimental Gerontology

Homeostasis is a key feature of the cellular lifespan. Its maintenance influences the rate of ageing and it is determined by several factors, including efficient proteolysis. The proteasome is the major cellular proteolytic machinery responsible for the degradation of both normal and damaged proteins. Alterations of proteasome function have been recorded in various biological phenomena including ageing and replicative senescence.

Author(s): 
Chondrogianni, Niki
Kapeta, Suzanne
Chinou, Ioanna
Vassilatou, Katerina
Papassideri, Issidora
Gonos, Efstathios S.
Publication Title: 
Advances in Experimental Medicine and Biology

Homeostasis is a key feature of cellular lifespan. Maintenance of cellular homeostasis influences the rate of aging and its efficiency is determined by the cooperation between protein stability and resistance to stress, protein refolding, protein repair and proteolysis of damaged proteins. Protein degradation is predominately catalyzed by the proteasome which is responsible for cell clearance of abnormal, denatured or in general damaged proteins as well as for the regulated degradation of short-lived proteins.

Author(s): 
Chondrogianni, Niki
Gonos, Efstathios S.
Publication Title: 
PLoS genetics

Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking.

Author(s): 
Kruegel, Undine
Robison, Brett
Dange, Thomas
Kahlert, G¸nther
Delaney, Joe R.
Kotireddy, Soumya
Tsuchiya, Mitsuhiro
Tsuchiyama, Scott
Murakami, Christopher J.
Schleit, Jennifer
Sutphin, George
Carr, Daniel
Tar, Krisztina
Dittmar, Gunnar
Kaeberlein, Matt
Kennedy, Brian K.
Schmidt, Marion
Publication Title: 
Nature

Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture. Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance.

Author(s): 
Vilchez, David
Boyer, Leah
Morantte, Ianessa
Lutz, Margaret
Merkwirth, Carsten
Joyce, Derek
Spencer, Brian
Page, Lesley
Masliah, Eliezer
Berggren, W. Travis
Gage, Fred H.
Dillin, Andrew
Publication Title: 
Annual Review of Genetics

The fruit fly, Drosophila melanogaster, is an excellent organism for the study of the genetic and molecular basis of metazoan development. Drosophila provides numerous tools and reagents to unravel the molecular and cellular functions of genes that cause human disease, and the past decade has witnessed a significant expansion of the study of neurodegenerative disease mechanisms in flies. Here we review the interplay between oxidative stress and neuronal toxicity.

Author(s): 
Jaiswal, M.
Sandoval, H.
Zhang, K.
Bayat, V.
Bellen, H. J.
Publication Title: 
Biochimica Et Biophysica Acta

Hyperglycemia is a hallmark of diabetes that is associated with diabetic complications and a reduction of lifespan. Using the mev-1 mutant of the nematode Caenorhabditis elegans we here tried to identify molecular mechanisms underlying the lifespan reducing effects of glucose. The lowest glucose concentration tested (10mM) caused a significant lifespan reduction at 37∞C and was used to assess effects on mitochondrial efficiency, formation of protein carbonyls and levels of methylglyoxal, a precursor of advanced glycation end products (AGEs).

Author(s): 
Fitzenberger, Elena
Boll, Michael
Wenzel, Uwe
Publication Title: 
Aging Cell

Proteostasis is critical for maintaining cell function and proteome stability may play an important role in human embryonic stem cell (hESC) immortality. Notably, hESC populations exhibit a high assembly of active proteasomes, a key node of the proteostasis network. FOXO4, an insulin/IGF-1 responsive transcription factor, regulates proteasome activity in hESCs. We find that loss of FOXO4 reduces the potential of hESCs to differentiate into neural lineages. Therefore, FOXO4 crosses evolutionary boundaries and links hESC function to invertebrate longevity modulation.

Author(s): 
Vilchez, David
Boyer, Leah
Lutz, Margaret
Merkwirth, Carsten
Morantte, Ianessa
Tse, Chris
Spencer, Brian
Page, Lesley
Masliah, Eliezer
Berggren, William Travis
Gage, Fred H.
Dillin, Andrew

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