Regulation of NF-κB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)

Mazumdar, Tuhina; Gorgun, Falih M.; Sha, Youbao; Tyryshkin, Alexey; Zeng, Shenyan; Hartmann‐Petersen, Rasmus; Jørgensen, Jakob Ploug; Hendil, Klavs B.; Eissa, N. Tony

doi:10.1073/pnas.0913495107

Cited by 62 publications

(57 citation statements)

References 29 publications

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“…These in vitro results indicate that active chain trimming is necessary to promote proteasomal degradation of some, if not all, proteins conjugated with Lys-48-linked polyUb chain(s). Consistent with our results, inducible nitric oxide synthase and IB-␣ were recently found as physiological substrates of Uch37-mediated proteasomal degradation (16), in which IB-␣ is known to be modified with Lys-48-linked polyUb chains by the SCF ␤TrCP E3 ligase for proteasomal degradation during NFB activation (34).…”

Section: Discussionsupporting

confidence: 78%

“…In yeast cells, depletion of Ubp6 impairs degradation of some proteasomal substrates, including Ub-Pro-␤-galactosidase (9). In mammalian cells, RNAi-medi-ated knockdown of Uch37, Usp14, Adrm1 (the Uch37 activator (13)(14)(15)), or their combinations were found to impair proteasomal degradation in cells, at least for those examined substrates (10,13,16). Moreover, inhibition of the chain trimming activity abolishes efficient degradation of some Lys-48-linked polyubiquitinated proteins in in vitro reconstituted degradation assays (17).…”

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confidence: 99%

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Ubiquitin Chain Trimming Recycles the Substrate Binding Sites of the 26 S Proteasome and Promotes Degradation of Lysine 48-linked Polyubiquitin Conjugates

Zhang¹,

Jacobson²,

MacFadden

et al. 2011

Journal of Biological Chemistry

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The 26 S proteasome possesses two distinct deubiquitinating activities. The ubiquitin (Ub) chain amputation activity removes the entire polyUb chain from the substrates. The Ub chain trimming activity progressively cleaves a polyUb chain from the distal end. The Ub chain amputation activity mediates degradation-coupled deubiquitination. The Ub chain trimming activity can play a supportive or an inhibitory role in degradation, likely depending on features of the substrates. How Ub chain trimming assists degradation is not clear. We find that inhibition of the chain trimming activity of the 26 S proteasome with Ub aldehyde significantly inhibits degradation of Ub 4 (Lys-48)-UbcH10 and causes accumulation of free Ub 4 (generated from chain amputation) that can be retained on the proteasome. Also, a non-trimmable Lys-48-mimic Ub 4 efficiently targets UbcH10 to the 26 S proteasome, but it cannot support efficient degradation of UbcH10 compared with regular Lys-48 Ub 4 . These results indicate that polyUb chain trimming promotes proteasomal degradation of Lys-48-linked substrates. Mechanistically, we propose that Ub chain trimming cleaves the proteasome-bound Lys-48-linked polyUb chains, which vacates the Ub binding sites of the 26 S proteasome, thus allowing continuous substrate loading.

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

Ubiquitin Chain Trimming Recycles the Substrate Binding Sites of the 26 S Proteasome and Promotes Degradation of Lysine 48-linked Polyubiquitin Conjugates

Zhang¹,

Jacobson²,

MacFadden

et al. 2011

Journal of Biological Chemistry

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“…Several studies, performed both in vivo and in vitro, have suggested that UCH37 can suppress protein degradation (12)(13)(14). In contrast, a recent study has suggested that UCH37 may instead promote the degradation of specific proteasome substrates, thus working similarly to RPN11 (26). We know too little to resolve these seeming contradictions.…”

Section: Usp14 and Uch37: How Do They Compare?mentioning

confidence: 69%

Trimming of Ubiquitin Chains by Proteasome-associated Deubiquitinating Enzymes

Lee

Hanna

et al. 2011

Molecular & Cellular Proteomics

218

250

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The proteasome generally recognizes substrate via its multiubiquitin chain followed by ATP-dependent unfolding and translocation of the substrate from the regulatory particle into the proteolytic core particle to be degraded. Substrate-bound ubiquitin groups are for the most part not delivered to the core particle and broken down together with substrate but instead recovered as intact free ubiquitin and ubiquitin chains. Substrate deubiquitination on the proteasome is mediated by three distinct deubiquitinating enzymes associated with the regulatory particle: RPN11, UCH37, and USP14. RPN11 cleaves at the base of the ubiquitin chain where it is linked to the substrate, whereas UCH37 and apparently USP14 mediate a stepwise removal of ubiquitin from the substrate by disassembling the chain from its distal tip. In contrast to UCH37 and USP14, RPN11 shows degradation-coupled activity; RPN11-mediated deubiquitination is apparently delayed until the proteasome is committed to degrade the substrate. Accordingly, RPN11-mediated deubiquitination promotes substrate degradation. In contrast, removal of ubiquitin prior to commitment could antagonize substrate degradation by promoting substrate dissociation from the proteasome. Emerging evidence suggests that USP14 and UCH37 can both suppress substrate degradation in this way. One line of study has shown that small molecule USP14 inhibitors can enhance proteasome function in cells, which is consistent with this model. Enhancing protein degradation could potentially have therapeutic applications for diseases involving toxic proteins that are proteasome substrates.

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“…Previous work demonstrated that after 20 h of macrophage activation, iNOS is polyubiquitinated and targeted for proteasomal degradation (22). In addition, the DUB UCH37 promoted degradation of ubiquitinated iNOS via the 20S proteasome (23). WP1130 is known to target several DUBs, including UCH37, in lymphoma and HEK293 cells (18).…”

Section: Discussionmentioning

confidence: 99%

A Small Molecule Deubiquitinase Inhibitor Increases Localization of Inducible Nitric Oxide Synthase to the Macrophage Phagosome and Enhances Bacterial Killing

et al. 2011

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Macrophages are key mediators of antimicrobial defense and innate immunity. Innate intracellular defense mechanisms can be rapidly regulated at the posttranslational level by the coordinated addition and removal of ubiquitin by ubiquitin ligases and deubiquitinases (DUBs). While ubiquitin ligases have been extensively studied, the contribution of DUBs to macrophage innate immune function is incompletely defined. We therefore employed a small molecule DUB inhibitor, WP1130, to probe the role of DUBs in the macrophage response to bacterial infection. Treatment of activated bone marrow-derived macrophages (BMM) with WP1130 significantly augmented killing of the intracellular bacterial pathogen Listeria monocytogenes. WP1130 also induced killing of phagosome-restricted bacteria, implicating a bactericidal mechanism associated with the phagosome, such as the inducible nitric oxide synthase (iNOS). WP1130 had a minimal antimicrobial effect in macrophages lacking iNOS, indicating that iNOS is an effector mechanism for WP1130-mediated bacterial killing. Although overall iNOS levels were not notably different, we found that WP1130 significantly increased colocalization of iNOS with the Listeria-containing phagosome during infection. Taken together, our data indicate that the deubiquitinase inhibitor WP1130 increases bacterial killing in macrophages by enhancing iNOS localization to the phagosome and suggest a potential role for ubiquitin regulation in iNOS trafficking.

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Regulation of NF-κB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)

Cited by 62 publications

References 29 publications

Ubiquitin Chain Trimming Recycles the Substrate Binding Sites of the 26 S Proteasome and Promotes Degradation of Lysine 48-linked Polyubiquitin Conjugates

Ubiquitin Chain Trimming Recycles the Substrate Binding Sites of the 26 S Proteasome and Promotes Degradation of Lysine 48-linked Polyubiquitin Conjugates

Trimming of Ubiquitin Chains by Proteasome-associated Deubiquitinating Enzymes

A Small Molecule Deubiquitinase Inhibitor Increases Localization of Inducible Nitric Oxide Synthase to the Macrophage Phagosome and Enhances Bacterial Killing

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