The phagosome and redox control of antigen processing

Ewanchuk, Benjamin W.; Yates, Robin M.

doi:10.1016/j.freeradbiomed.2018.03.040

Cited by 21 publications

(19 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In any case, our data show that PIKfyve-mediated phagosomal maturation affects the activity of cysteine cathepsins via NOX-produced ROS, and this can modulate the epitope repertoire for MHC presentation (Balce et al., 2011, Rybicka et al., 2010, Rybicka et al., 2012). Because NOX2 mediates the disulfide reduction of protein antigens (Ewanchuk and Yates, 2018), the effects of NOX2-produced ROS on antigen processing will be even more pronounced. Only linear peptide/protein stretches are accessible to proteases for cleavage, hence all inter- and intra-disulfide bonds have to be reduced before antigen processing (Bogunovic et al., 2010), as has been also demonstrated for MHC class II with model antigens (Jensen, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Only linear peptide/protein stretches are accessible to proteases for cleavage, hence all inter- and intra-disulfide bonds have to be reduced before antigen processing (Bogunovic et al., 2010), as has been also demonstrated for MHC class II with model antigens (Jensen, 1991). γ-Interferon-inducible lysosomal thiol reductase activity can be inhibited by ROS, and this may cause different antigen processing patterns leading to altered repertoires of peptides for presentation, because some of the proteins cannot be unfolded and are therefore not accessible to proteinases for degradation (Ewanchuk and Yates, 2018).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation

et al. 2019

View full text Add to dashboard Cite

SummaryAntigen presentation to T cells in major histocompatibility complex class II (MHC class II) requires the conversion of early endo/phagosomes into lysosomes by a process called maturation. Maturation is driven by the phosphoinositide kinase PIKfyve. Blocking PIKfyve activity by small molecule inhibitors caused a delay in the conversion of phagosomes into lysosomes and in phagosomal acidification, whereas production of reactive oxygen species (ROS) increased. Elevated ROS resulted in reduced activity of cathepsin S and B, but not X, causing a proteolytic defect of MHC class II chaperone invariant chain Ii processing. We developed a novel universal MHC class II presentation assay based on a bio-orthogonal “clickable” antigen and showed that MHC class II presentation was disrupted by the inhibition of PIKfyve, which in turn resulted in reduced activation of CD4+ T cells. Our results demonstrate a key role of PIKfyve in the processing and presentation of antigens, which should be taken into consideration when targeting PIKfyve in autoimmune disease and cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation

et al. 2019

View full text Add to dashboard Cite

show abstract

“…These results support that there is a difference in chemical reactivity of the invariant thiol group of their active site, although cathepsins L, S and K are enzymatically and structurally close. On the other hand, NADPH oxidase 2 (NOX2), which is found in the acidic compartments of antigenpresenting cells (i.e., macrophages and dendritic cells) and is involved in the synthesis of O2 − , was reported to play a pivotal role during MHC class II antigen presentation through the redox control of antigen processing by cysteine cathepsins [150][151][152][153][154]. A new strategy that consists of generating ROS from redox cyclic compounds (RCCs) was proposed to target cysteine cathepsins [155].…”

Section: Inactivation By Reactive Oxygen Speciesmentioning

confidence: 99%

Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

Lalmanach

Saidi

Bigot

et al. 2020

IJMS

View full text Add to dashboard Cite

Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation via their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Although the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Besides an introductory chapter and peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated with the regulation of cysteine cathepsins by redox balance and by oxidants (e.g., Michael acceptors, reactive oxygen, and nitrogen species).

show abstract

“…GSSG/GSH ratio or oxygenations (Lockwood 2002). A dedicated lysosomal reductase maintains reduction of disulfide bonds and activates CysHis/CysHis(X) cathepsins (see Rybicka et al 2010; Balce et al 2014; Allan and Yates 2015; Ewanchuk and Yates 2018). In addition to metal and redox regulation, the vacuolar proton pump (V-ATPase) is a major influence on the reaction rates of lysosomal CysCts, and the activation of pro-protease zymogens.…”

Section: Pharmacological Recruitment Of Endogenous Zn2+ To Intervene mentioning

confidence: 99%

Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn2+ to inhibit cysteinyl cathepsins: review and implications

Lockwood

2019

Biometals

View full text Add to dashboard Cite

Excessive activities of cysteinyl cathepsins (CysCts) contribute to the progress of many diseases; however, therapeutic inhibition has been problematic. Zn 2 + is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa) triads. Biguanide forms bidentate metal complexes through the two imino nitrogens. Here, it is discussed that phenformin (phenylethyl biguanide) is a model for recruitment of endogenous Zn 2 + to inhibit CysHis/CysHis(X) peptidolysis. Phenformin is a Zn 2 + -interactive, anti-proteolytic agent in bioassay of living tissue. Benzoyl- l -arginine amide (BAA) is a classical substrate of papain-like proteases; the amide bond is scissile. In this review, the structures of BAA and the phenformin-Zn 2 + complex were compared in silico. Their chemistry and dimensions are discussed in light of the active sites of papain-like proteases. The phenyl moieties of both structures bind to the “S2” substrate-binding site that is typical of many proteases. When the phenyl moiety of BAA binds to S2, then the scissile amide bond is directed to the position of the thiolate-imidazolium ion pair, and is then hydrolyzed. However, when the phenyl moiety of phenformin binds to S2, then the coordinated Zn 2 + is directed to the identical position; and catalysis is inhibited. Phenformin stabilizes a “Zn 2 + sandwich” between the drug and protease active site. Hundreds of biguanide derivatives have been synthesized at the 1 and 5 nitrogen positions; many more are conceivable. Various substituent moieties can register with various arrays of substrate-binding sites so as to align coordinated Zn 2 + with catalytic partners of diverse proteases. Biguanide is identified here as a modifiable pharmacophore for synthesis of therapeutic CysCt inhibitors with a wide range of potencies and specificities. Graphical abstract Phenformin-Zn 2+ Complex

show abstract

The phagosome and redox control of antigen processing

Cited by 21 publications

References 93 publications

The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation

The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation

Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn2+ to inhibit cysteinyl cathepsins: review and implications

Contact Info

Product

Resources

About