Targeting proteasomes in infectious organisms to combat disease

Bibo-Verdugo, Betsaida; Jiang, Zhenze; Caffrey, Conor R.; O’Donoghue, Anthony J.

doi:10.1111/febs.14029

Cited by 47 publications

(44 citation statements)

References 114 publications

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“…However, in contrast to Pst infection, MG132 treatment is still sufficient to inactivate the proteasome in atg mutants (Marshall et al, 2016), suggesting different modes of HopM1 and MG132 action. Indeed, HopM1 is mainly associated with the regulatory particle of the 26S proteasome (Üstün et al, 2016), while MG132 targets its catalytic subunits (Bibo-Verdugo et al, 2017). Hence, an efficient block of proteasome activity during Pst infection requires a functional proteaphagy pathway involving the core autophagy machinery (ATG2, ATG5, and ATG7) and cargo receptor (RPN10).…”

Section: Discussionmentioning

confidence: 99%

Bacteria Exploit Autophagy for Proteasome Degradation and Enhanced Virulence in Plants

et al. 2018

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Autophagy and the ubiquitin-proteasome system (UPS) are two major protein degradation pathways implicated in the response to microbial infections in eukaryotes. In animals, the contribution of autophagy and the UPS to antibacterial immunity is well documented and several bacteria have evolved measures to target and exploit these systems to the benefit of infection. In plants, the UPS has been established as a hub for immune responses and is targeted by bacteria to enhance virulence. However, the role of autophagy during plant-bacterial interactions is less understood. Here, we have identified both pro- and antibacterial functions of autophagy mechanisms upon infection of with virulent pv DC3000 (). We show that activates autophagy in a type III effector (T3E)-dependent manner and stimulates the autophagic removal of proteasomes (proteaphagy) to support bacterial proliferation. We further identify the T3E Hrp outer protein M1 (HopM1) as a principle mediator of autophagy-inducing activities during infection. In contrast to the probacterial effects of-induced proteaphagy, NEIGHBOR OF BRCA1-dependent selective autophagy counteracts disease progression and limits the formation of HopM1-mediated water-soaked lesions. Together, we demonstrate that distinct autophagy pathways contribute to host immunity and bacterial pathogenesis during infection and provide evidence for an intimate crosstalk between proteasome and autophagy in plant-bacterial interactions.

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Section: Discussionmentioning

confidence: 99%

Bacteria Exploit Autophagy for Proteasome Degradation and Enhanced Virulence in Plants

et al. 2018

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“…Several bacterial, viral, protozoan and fungal proteases trigger inflammation by activating the intrinsic coagulation pathway [102], or act as procoagulants by non-canonical, direct activation of prothrombin [179]. Large panels of small-molecule inhibitors of the proteasome in pathogenic organisms are currently being screened for potential therapeutic benefit and minimal toxicity toward the cellular machinery of the host [180]. Bacterial infections are associated with increased thrombotic risk, however this correlation is not restricted to pathogenic bacteria.…”

Section: Proteases and Diseasementioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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“…The ubiquitin-proteasome pathway (UPP) regulates a variety of critical cellular processes such as transcriptional control, cell cycle progression, protein quality control, oncogenesis, apoptosis, and stress response. Dysfunction of the UPP is associated with many diseases, including cancer, neurodegeneration, autoimmune and inflammatory response, and infectious diseases [1,[16][17][18][19]. As a result of its key functional role, the UPP represents an attractive drug target that has been extensively investigated during the last two decades [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Effect of Ferulic Acid, a Phenolic Inducer of Fungal Laccase, on 26S Proteasome Activities In Vitro

Swatek

Staszczak

2020

IJMS

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The 26S proteasome is an ATP-dependent protease complex (2.5 MDa) that degrades most cellular proteins in Eukaryotes, typically those modified by a polyubiquitin chain. The proteasome-mediated proteolysis regulates a variety of critical cellular processes such as transcriptional control, cell cycle, oncogenesis, apoptosis, protein quality control, and stress response. Previous studies conducted in our laboratory have shown that 26S proteasomes are involved in the regulation of ligninolytic enzymes (such as laccase) in white-rot fungi in response to nutrient starvation, cadmium exposure, and ER stress. Laccases are useful biocatalysts for a wide range of biotechnological applications. The goal of the current study was to determine the effect of ferulic acid (4-hydroxy-3-methoxycinnamic acid), a phenolic compound known to induce some ligninolytic enzymes, on proteasomes isolated from mycelia of the wood-decomposing basidiomycete Trametes versicolor. The peptidase activities of 26S proteasomes were assayed by measuring the hydrolysis of fluorogenic peptide substrates specific for each active site: Suc-LLVY-AMC, Z-GGR-AMC and Z-LLE-AMC for chymotrypsin-like, trypsin-like, and caspase-like site, respectively. Ferulic acid affected all peptidase activities of the 26S fungal proteasomes in a concentration-dependent manner. A possible inhibitory effect of ferulic acid on peptidase activities of the 26S human proteasomes was tested as well. Moreover, the ability of ferulic acid to inhibit (at concentrations known to induce laccase activity in white-rot fungi) the rate of 26S proteasome-catalyzed degradation of a model full-length protein substrate (β-casein) was demonstrated by a fluorescamine assay and by a gel-electrophoretic analysis. Our findings provide new insights into the role of ferulic acid in lignin-degrading fungi. However, the detailed molecular mechanisms involved remain to be elucidated by future studies.

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Targeting proteasomes in infectious organisms to combat disease

Cited by 47 publications

References 114 publications

Bacteria Exploit Autophagy for Proteasome Degradation and Enhanced Virulence in Plants

Bacteria Exploit Autophagy for Proteasome Degradation and Enhanced Virulence in Plants

Proteases: Pivot Points in Functional Proteomics

Effect of Ferulic Acid, a Phenolic Inducer of Fungal Laccase, on 26S Proteasome Activities In Vitro

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