scholarly journals Contribution of the Clp Protease to Bacterial Survival and Mitochondrial Homoeostasis

2021 ◽  
pp. 1-20
Author(s):  
Astrid Illigmann ◽  
Yvonne Thoma ◽  
Stefan Pan ◽  
Laura Reinhardt ◽  
Heike Brötz-Oesterhelt
Keyword(s):  
Quality Control ◽  
Regulatory Networks ◽  
Protein Quality ◽  
Environmental Changes ◽  
Protein Quality Control ◽  
Adaptor Proteins ◽  
Degradation Process ◽  
Eukaryotic Cells ◽  
Bacterial Survival ◽  
Clp Protease

Fast adaptation to environmental changes ensures bacterial survival, and proteolysis represents a key cellular process in adaptation. The Clp protease system is a multi-component machinery responsible for protein homoeostasis, protein quality control, and targeted proteolysis of transcriptional regulators in prokaryotic cells and prokaryote-derived organelles of eukaryotic cells. A functional Clp protease complex consists of the tetradecameric proteolytic core ClpP and a hexameric ATP-consuming Clp-ATPase, several of which can associate with the same proteolytic core. Clp-ATPases confer substrate specificity by recognising specific degradation tags, and further selectivity is conferred by adaptor proteins, together allowing for a fine-tuned degradation process embedded in elaborate regulatory networks. This review focuses on the contribution of the Clp protease system to prokaryotic survival and summarises the current state of knowledge for exemplary bacteria in an increasing degree of interaction with eukaryotic cells. Starting from free-living bacteria as exemplified by a non-pathogenic and a pathogenic member of the Firmicutes, i.e., <i>Bacillus subtilis</i> and <i>Staphylococcus aureus</i>, respectively, we turn our attention to facultative and obligate intracellular bacterial pathogens, i.e., <i>Mycobacterium tuberculosis, Listeria monocytogenes,</i> and <i>Chlamydia trachomatis</i>, and conclude with mitochondria. Under stress conditions, the Clp protease system exerts its pivotal role in the degradation of damaged proteins and controls the timing and extent of the heat-shock response by regulatory proteolysis. Key regulators of developmental programmes like natural competence, motility, and sporulation are also under Clp proteolytic control. In many pathogenic species, the Clp system is required for the expression of virulence factors and essential for colonising the host. In accordance with its evolutionary origin, the human mitochondrial Clp protease strongly resembles its bacterial counterparts, taking a central role in protein quality control and homoeostasis, energy metabolism, and apoptosis in eukaryotic cells, and several cancer cell types depend on it for proliferation.

scholarly journals Loss of protein quality control gene UBR1 sensitizes Saccharomyces cerevisiae to the aminoglycoside hygromycin B

Fine Focus ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. 76-83
Author(s):  
Avery M. Runnebohm ◽  
Melissa D. Evans ◽  
Adam E. Richardson ◽  
Samantha M. Turk ◽  
James B. Olesen ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Eukaryotic Cells ◽  
Hygromycin B ◽  
Eukaryotic Microorganism ◽  
Human Enzyme ◽  
A Site

Ubr1 is a conserved ubiquitin ligase involved in the degradation of aberrant proteins in eukaryotic cells. The human enzyme is found mutated in patients with Johanson-Blizzard syndrome. We hypothesized that Ubr1 is necessary for optimal cellular fitness in conditions associated with elevated abundance of aberrant and misfolded proteins. Indeed, we found that loss of Ubr1 in the model eukaryotic microorganism Saccharomyces cerevisiae strongly sensitizes cells to hygromycin B, which reduces translational fidelity by causing ribosome A site distortion. Our results are consistent with a prominent role for Ubr1 in protein quality control. We speculate that disease manifestations in patients with Johanson-Blizzard syndrome are linked, at least in part, to defects in protein quality control caused by loss of Ubr1 function.

scholarly journals RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control

2021 ◽  
Author(s):  
Harihar Milaganur Mohan ◽  
Amit Pithadia ◽  
Hanna Trzeciakiewicz ◽  
Emily V. Crowley ◽  
Regina Pacitto ◽  
...  
Keyword(s):  
Quality Control ◽  
Mouse Brain ◽  
Protein Quality ◽  
Nuclear Translocation ◽  
Protein Quality Control ◽  
Adaptor Proteins ◽  
Ubiquitin Proteasome System ◽  
Subnuclear Localization

AbstractThe brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington’s disease where it promotes the clearance of mutant Huntingtin protein. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, RTL8 promotes nuclear translocation of UBQLN2. UBQLN2 and RTL8 colocalize within ubiquitin-enriched subnuclear structures containing PQC components. The robust effect of RTL8 on the nuclear translocation and subnuclear localization of UBQLN2 does not extend to the other brain-expressed ubiquilins, UBQLN1 and UBQLN4. Moreover, compared to UBQLN1 and UBQLN4, UBQLN2 preferentially stabilizes RTL8 levels in human cell lines and in mouse brain, supporting functional heterogeneity among UBQLNs. As a novel UBQLN2 interactor that recruits UBQLN2 to specific nuclear compartments, RTL8 may regulate UBQLN2 function in nuclear protein quality control.

scholarly journals UPF1: From mRNA Surveillance to Protein Quality Control

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 995
Author(s):  
Hyun Jung Hwang ◽  
Yeonkyoung Park ◽  
Yoon Ki Kim
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Eukaryotic Cells ◽  
Mediated Communication ◽  
Premature Termination Codons ◽  
Mrna Surveillance ◽  
Ubiquitin Proteasome ◽  
Nonsense Mediated Mrna Decay

Selective recognition and removal of faulty transcripts and misfolded polypeptides are crucial for cell viability. In eukaryotic cells, nonsense-mediated mRNA decay (NMD) constitutes an mRNA surveillance pathway for sensing and degrading aberrant transcripts harboring premature termination codons (PTCs). NMD functions also as a post-transcriptional gene regulatory mechanism by downregulating naturally occurring mRNAs. As NMD is activated only after a ribosome reaches a PTC, PTC-containing mRNAs inevitably produce truncated and potentially misfolded polypeptides as byproducts. To cope with the emergence of misfolded polypeptides, eukaryotic cells have evolved sophisticated mechanisms such as chaperone-mediated protein refolding, rapid degradation of misfolded polypeptides through the ubiquitin–proteasome system, and sequestration of misfolded polypeptides to the aggresome for autophagy-mediated degradation. In this review, we discuss how UPF1, a key NMD factor, contributes to the selective removal of faulty transcripts via NMD at the molecular level. We then highlight recent advances on UPF1-mediated communication between mRNA surveillance and protein quality control.

Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

2021 ◽  
pp. 153537022199981
Author(s):  
Chamithi Karunanayake ◽  
Richard C Page
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Structural Features ◽  
Cellular Protein ◽  
Mechanisms Of Action ◽  
Control Mechanisms ◽  
Nucleotide Exchange ◽  
Domain Organization ◽  
Nucleotide Exchange Factors

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

scholarly journals The protein quality control and neurodegeneration

2003 ◽  
Vol 122 (1) ◽  
pp. 30-36 ◽  
Author(s):  
Keiji TANAKA ◽  
Shigeo MURATA
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control
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