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Title: An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world’s most devastating pathogens.

Authors:
 [1];  [2];  [3];  [2];  [4];  [5];  [6];  [6];  [5];  [3];  [4];  [1]
  1. New York Univ. School of Medicine, New York, NY (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
  3. Harvard Medical School, Boston, MA (United States)
  4. Brookhaven National Lab. (BNL), Upton, NY (United States); Stony Brook Univ., NY (United States)
  5. Netherlands Cancer Inst., Amsterdam (Netherlands)
  6. Univ. of Washington, Seattle, WA (United States)
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
National Institute of Health, New York, NY (United States)
OSTI Identifier:
1215607
Report Number(s):
BNL-108345-2015-JA
Journal ID: ISSN 1091-6490; 400412000
Grant/Contract Number:  
SC00112704
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 112; Journal Issue: 14; Journal ID: ISSN 1091-6490
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; mycobacterium; tuberculosis; proteasome; activator; degradation

Citation Formats

Jastrab, Jordan B., Wang, Tong, Murphy, J. Patrick, Bai, Lin, Hu, Kuan, Merkx, Remco, Huang, Jessica, Chatterjee, Champak, Ovaa, Huib, Gygi, Steven P., Li, Huilin, and Darwin, K. Heran. An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis. United States: N. p., 2015. Web. doi:10.1073/pnas.1423319112.
Jastrab, Jordan B., Wang, Tong, Murphy, J. Patrick, Bai, Lin, Hu, Kuan, Merkx, Remco, Huang, Jessica, Chatterjee, Champak, Ovaa, Huib, Gygi, Steven P., Li, Huilin, & Darwin, K. Heran. An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis. United States. doi:10.1073/pnas.1423319112.
Jastrab, Jordan B., Wang, Tong, Murphy, J. Patrick, Bai, Lin, Hu, Kuan, Merkx, Remco, Huang, Jessica, Chatterjee, Champak, Ovaa, Huib, Gygi, Steven P., Li, Huilin, and Darwin, K. Heran. Mon . "An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis". United States. doi:10.1073/pnas.1423319112. https://www.osti.gov/servlets/purl/1215607.
@article{osti_1215607,
title = {An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis},
author = {Jastrab, Jordan B. and Wang, Tong and Murphy, J. Patrick and Bai, Lin and Hu, Kuan and Merkx, Remco and Huang, Jessica and Chatterjee, Champak and Ovaa, Huib and Gygi, Steven P. and Li, Huilin and Darwin, K. Heran},
abstractNote = {Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world’s most devastating pathogens.},
doi = {10.1073/pnas.1423319112},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 14,
volume = 112,
place = {United States},
year = {Mon Mar 23 00:00:00 EDT 2015},
month = {Mon Mar 23 00:00:00 EDT 2015}
}

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Cited by: 12 works
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