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

Tuhina Mazumdar; F Murat Gorgun; Youbao Sha; Alexey Tyryshkin; Shenyan Zeng; Rasmus Hartmann-Petersen; Jakob Ploug Jørgensen; Klavs B Hendil; N Tony Eissa

doi:10.1073/pnas.0913495107

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

Tuhina Mazumdar, F Murat Gorgun, Youbao Sha, Alexey Tyryshkin, Shenyan Zeng, Rasmus Hartmann-Petersen, Jakob Ploug Jørgensen, Klavs B Hendil, N Tony Eissa

Biomolecular Sciences

52 Citations (Scopus)

Abstract

Human Rpn13, also known as adhesion regulating molecule 1 (ADRM1), was recently identified as a novel 19S proteasome cap-associated protein, which recruits the deubiquitinating enzyme UCH37 to the 26S proteasome. Knockdown of Rpn13 by siRNA does not lead to global accumulation of ubiquitinated cellular proteins or changes in proteasome expression, suggesting that Rpn13 must have a specialized role in proteasome function. Thus, Rpn13 participation in protein degradation, by recruiting UCH37, is rather selective to specific proteins whose degradation critically depends on UCH37 deubiquitination activity. The specific substrates for the Rpn13/UCH37 complex have not been determined. Because of a previous discovery of an interaction between Rpn13 and inducible nitric oxide synthase (iNOS), we hypothesized that iNOS is one of the substrates for the Rpn13/UCH37 complex. In this study,we show that Rpn13 is involved in iNOS degradation and is required for iNOS interaction with the deubiquitination protein UCH37. Furthermore, we discovered that IκB-α, a protein whose proteasomal degradation activates the transcription factor NF-κB, is also a substrate for the Rpn13/UCH37 complex. Thus, this study defines two substrates, with important roles in inflammation and host defense for the Rpn13/UCH37 pathway.

Original language	English
Journal	Proceedings of the National Academy of Science of the United States of America
Volume	107
Issue number	31
Pages (from-to)	13854-9
Number of pages	5
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.0913495107
Publication status	Published - 3 Aug 2010

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Mazumdar, T., Gorgun, F. M., Sha, Y., Tyryshkin, A., Zeng, S., Hartmann-Petersen, R., Jørgensen, J. P., Hendil, K. B., & Eissa, N. T. (2010). Regulation of NF-kappaB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13). Proceedings of the National Academy of Science of the United States of America, 107(31), 13854-9. https://doi.org/10.1073/pnas.0913495107

Regulation of NF-kappaB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13). / Mazumdar, Tuhina; Gorgun, F Murat; Sha, Youbao et al.

In: Proceedings of the National Academy of Science of the United States of America, Vol. 107, No. 31, 03.08.2010, p. 13854-9.

Research output: Contribution to journal › Journal article › Research › peer-review

Mazumdar, T, Gorgun, FM, Sha, Y, Tyryshkin, A, Zeng, S, Hartmann-Petersen, R, Jørgensen, JP, Hendil, KB & Eissa, NT 2010, 'Regulation of NF-kappaB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)', Proceedings of the National Academy of Science of the United States of America, vol. 107, no. 31, pp. 13854-9. https://doi.org/10.1073/pnas.0913495107

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title = "Regulation of NF-kappaB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)",

abstract = "Human Rpn13, also known as adhesion regulating molecule 1 (ADRM1), was recently identified as a novel 19S proteasome cap-associated protein, which recruits the deubiquitinating enzyme UCH37 to the 26S proteasome. Knockdown of Rpn13 by siRNA does not lead to global accumulation of ubiquitinated cellular proteins or changes in proteasome expression, suggesting that Rpn13 must have a specialized role in proteasome function. Thus, Rpn13 participation in protein degradation, by recruiting UCH37, is rather selective to specific proteins whose degradation critically depends on UCH37 deubiquitination activity. The specific substrates for the Rpn13/UCH37 complex have not been determined. Because of a previous discovery of an interaction between Rpn13 and inducible nitric oxide synthase (iNOS), we hypothesized that iNOS is one of the substrates for the Rpn13/UCH37 complex. In this study,we show that Rpn13 is involved in iNOS degradation and is required for iNOS interaction with the deubiquitination protein UCH37. Furthermore, we discovered that IκB-α, a protein whose proteasomal degradation activates the transcription factor NF-κB, is also a substrate for the Rpn13/UCH37 complex. Thus, this study defines two substrates, with important roles in inflammation and host defense for the Rpn13/UCH37 pathway.",

author = "Tuhina Mazumdar and Gorgun, {F Murat} and Youbao Sha and Alexey Tyryshkin and Shenyan Zeng and Rasmus Hartmann-Petersen and J{\o}rgensen, {Jakob Ploug} and Hendil, {Klavs B} and Eissa, {N Tony}",

note = "Keywords: Animals; Carboxypeptidases; Cell Adhesion Molecules; Cell Line; Down-Regulation; Humans; Membrane Glycoproteins; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Protein Binding; RNA, Small Interfering",

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AU - Mazumdar, Tuhina

AU - Gorgun, F Murat

AU - Sha, Youbao

AU - Tyryshkin, Alexey

AU - Zeng, Shenyan

AU - Hartmann-Petersen, Rasmus

AU - Jørgensen, Jakob Ploug

AU - Hendil, Klavs B

AU - Eissa, N Tony

N1 - Keywords: Animals; Carboxypeptidases; Cell Adhesion Molecules; Cell Line; Down-Regulation; Humans; Membrane Glycoproteins; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Protein Binding; RNA, Small Interfering

PY - 2010/8/3

Y1 - 2010/8/3

N2 - Human Rpn13, also known as adhesion regulating molecule 1 (ADRM1), was recently identified as a novel 19S proteasome cap-associated protein, which recruits the deubiquitinating enzyme UCH37 to the 26S proteasome. Knockdown of Rpn13 by siRNA does not lead to global accumulation of ubiquitinated cellular proteins or changes in proteasome expression, suggesting that Rpn13 must have a specialized role in proteasome function. Thus, Rpn13 participation in protein degradation, by recruiting UCH37, is rather selective to specific proteins whose degradation critically depends on UCH37 deubiquitination activity. The specific substrates for the Rpn13/UCH37 complex have not been determined. Because of a previous discovery of an interaction between Rpn13 and inducible nitric oxide synthase (iNOS), we hypothesized that iNOS is one of the substrates for the Rpn13/UCH37 complex. In this study,we show that Rpn13 is involved in iNOS degradation and is required for iNOS interaction with the deubiquitination protein UCH37. Furthermore, we discovered that IκB-α, a protein whose proteasomal degradation activates the transcription factor NF-κB, is also a substrate for the Rpn13/UCH37 complex. Thus, this study defines two substrates, with important roles in inflammation and host defense for the Rpn13/UCH37 pathway.

AB - Human Rpn13, also known as adhesion regulating molecule 1 (ADRM1), was recently identified as a novel 19S proteasome cap-associated protein, which recruits the deubiquitinating enzyme UCH37 to the 26S proteasome. Knockdown of Rpn13 by siRNA does not lead to global accumulation of ubiquitinated cellular proteins or changes in proteasome expression, suggesting that Rpn13 must have a specialized role in proteasome function. Thus, Rpn13 participation in protein degradation, by recruiting UCH37, is rather selective to specific proteins whose degradation critically depends on UCH37 deubiquitination activity. The specific substrates for the Rpn13/UCH37 complex have not been determined. Because of a previous discovery of an interaction between Rpn13 and inducible nitric oxide synthase (iNOS), we hypothesized that iNOS is one of the substrates for the Rpn13/UCH37 complex. In this study,we show that Rpn13 is involved in iNOS degradation and is required for iNOS interaction with the deubiquitination protein UCH37. Furthermore, we discovered that IκB-α, a protein whose proteasomal degradation activates the transcription factor NF-κB, is also a substrate for the Rpn13/UCH37 complex. Thus, this study defines two substrates, with important roles in inflammation and host defense for the Rpn13/UCH37 pathway.

U2 - 10.1073/pnas.0913495107

DO - 10.1073/pnas.0913495107

M3 - Journal article

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SN - 0027-8424

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EP - 13859

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 31

ER -

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

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