Role of Proteasomes in Inflammation.
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ABSTRACT:
SUBMITTER: Goetzke CC
PROVIDER: S-EPMC8072576 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Protein turnover and homeostasis are regulated by the proteasomal system, which is critical for cell function and viability. Pluripotency of stem cells also relies on normal proteasomal activity that mitigates senescent phenotypes induced by intensive cell replications, as previously demonstrated in human bone marrow stromal cells. In this study, we investigated the role of proteasomes in self-renewal of neural progenitor cells (NPCs). Through both in vivo and in vitro analyses, we found that the expression of proteasomes was progressively decreased during aging. Likewise, proliferation and self-renewal of NPCs were also impaired in aged mice, suggesting that the down-regulation of proteasomes might be responsible for this senescent phenotype. Lowering proteasomal activity by loss-of-function manipulations mimicked the senescence of NPCs both in vitro and in vivo; conversely, enhancing proteasomal activity restored and improved self-renewal in aged NPCs. These results collectively indicate that proteasomes work as a key regulator in promoting self-renewal of NPCs. This potentially provides a promising therapeutic target for age-dependent neurodegenerative diseases.
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Project description:The evidence that nuclear proteins can be degraded by cytosolic proteasomes has received considerable experimental support. However, the presence of proteasome subunits in the nucleus also suggests that protein degradation could occur within this organelle. We determined that Sts1 can target proteasomes to the nucleus and facilitate the degradation of a nuclear protein. Specific sts1 mutants showed reduced nuclear proteasomes at the nonpermissive temperature. In contrast, high expression of Sts1 increased the levels of nuclear proteasomes. Sts1 targets proteasomes to the nucleus by interacting with Srp1, a nuclear import factor that binds nuclear localization signals. Deletion of the NLS in Sts1 prevented its interaction with Srp1 and caused proteasome mislocalization. In agreement with this observation, a mutation in Srp1 that weakened its interaction with Sts1 also reduced nuclear targeting of proteasomes. We reported that Sts1 could suppress growth and proteolytic defects of rad23? rpn10?. We show here that Sts1 suppresses a previously undetected proteasome localization defect in this mutant. Taken together, these findings explain the suppression of rad23? rpn10? by Sts1 and suggest that the degradation of nuclear substrates requires efficient proteasome localization.
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Project description:Proteasomes are self-compartmentalized energy-dependent proteolytic machines found in Archaea, Actinobacteria species of bacteria and eukaryotes. Proteasomes consist of two separate protein complexes, the core particle that hydrolyzes peptide bonds and an AAA+ ATPase domain responsible for the binding, unfolding and translocation of protein substrates into the core particle for degradation. Similarly to eukaryotes, proteasomes play a central role in protein degradation and can be essential in Archaea. Core particles associate with and utilize a variety of ATPase complexes to carry out protein degradation in Archaea. In actinobacterial species, such as Mycobacterium tuberculosis, proteasome-mediated degradation is associated with pathogenesis and does not appear to be essential. Interestingly, both actinobacterial species and Archaea use small proteins to covalently modify proteins, prokaryotic ubiquitin-like proteins (Pup) in Actinobacteria and ubiquitin-like small archaeal modifier proteins (SAMP) in Archaea. These modifications may play a role in proteasome targeting similar to the ubiquitin-proteasome system in eukaryotes.
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Project description:Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.
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Project description:We present a biochemical and crystallographic characterization of active site mutants of the yeast 20S proteasome with the aim to characterize substrate cleavage specificity, subunit intermediate processing, and maturation. beta1(Pre3), beta2(Pup1), and beta5(Pre2) are responsible for the postacidic, tryptic, and chymotryptic activity, respectively. The maturation of active subunits is independent of the presence of other active subunits and occurs by intrasubunit autolysis. The propeptides of beta6(Pre7) and beta7(Pre4) are intermediately processed to their final forms by beta2(Pup1) in the wild-type enzyme and by beta5(Pre2) and beta1(Pre3) in the beta2(Pup1) inactive mutants. A role of the propeptide of beta1(Pre3) is to prevent acetylation and thereby inactivation. A gallery of proteasome mutants that contain active site residues in the context of the inactive subunits beta3(Pup3), beta6(Pre7), and beta7(Pre4) show that the presence of Gly-1, Thr1, Asp17, Lys33, Ser129, Asp166, and Ser169 is not sufficient to generate activity.
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Project description:Regulated proteolysis is essential for the normal physiology of all organisms. While all eukaryotes and archaea use proteasomes for protein degradation, only certain orders of bacteria have proteasomes, whose functions are likely as diverse as the species that use them. In this review, we discuss the most recent developments in the understanding of how proteins are targeted to proteasomes for degradation, including ATP-dependent and -independent mechanisms, and the roles of proteasome-dependent degradation in protein quality control and the regulation of cellular physiology. Furthermore, we explore newly established functions of proteasome system accessory factors that function independently of proteolysis.
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Project description:Among its many functions, the ubiquitin-proteasome system regulates substrate-specific proteolysis during the cell cycle, apoptosis, and fertilization and in pathologies such as Alzheimer's disease, cancer, and liver cirrhosis. Proteasomes are present in human and boar spermatozoa, but little is known about the interactions of proteasomal subunits with other sperm proteins or structures. We have created a transgenic boar with green fluorescent protein (GFP) tagged 20S proteasomal core subunit ?-type 1 (PSMA1-GFP), hypothesizing that the PSMA1-GFP fusion protein will be incorporated into functional sperm proteasomes. Using direct epifluorescence imaging and indirect immunofluorescence detection, we have confirmed the presence of PSMA1-GFP in the sperm acrosome. Western blotting revealed a protein band corresponding to the predicted mass of PSMA1-GFP fusion protein (57 kDa) in transgenic spermatozoa. Transgenic boar fertility was confirmed by in vitro fertilization, resulting in transgenic blastocysts, and by mating, resulting in healthy transgenic offspring. Immunoprecipitation and proteomic analysis revealed that PSMA1-GFP copurifies with several acrosomal membrane-associated proteins (e.g., lactadherin/milk fat globule E8 and spermadhesin alanine-tryptophan-asparagine). The interaction of MFGE8 with PSMA1-GFP was confirmed through cross-immunoprecipitation. The identified proteasome-interacting proteins may regulate sperm proteasomal activity during fertilization or may be the substrates of proteasomal proteolysis during fertilization. Proteomic analysis also confirmed the interaction/coimmunoprecipitation of PSMA1-GFP with 13/14 proteasomal core subunits. These results demonstrate that the PSMA1-GFP was incorporated in the assembled sperm proteasomes. This mammal carrying green fluorescent proteasomes will be useful for studies of fertilization and wherever the ubiquitin-proteasome system plays a role in cellular function or pathology.
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Project description:Proteasomes are a class of protease that carry out the degradation of a specific set of cellular proteins. While essential for eukaryotic life, proteasomes are found only in a small subset of bacterial species. In this chapter, we present the current knowledge of bacterial proteasomes, detailing the structural features and catalytic activities required to achieve proteasomal proteolysis. We describe the known mechanisms by which substrates are doomed for degradation, and highlight potential non-degradative roles for components of bacterial proteasome systems. Additionally, we highlight several pathways of microbial physiology that rely on proteasome activity. Lastly, we explain the various gaps in our understanding of bacterial proteasome function and emphasize several opportunities for further study.
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