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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America (Online)
 [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)
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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.
Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
National Institute of Health, New York, NY (United States)
OSTI ID:
1215607
Report Number(s):
BNL--108345-2015-JA; 400412000
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America (Online), Journal Name: Proceedings of the National Academy of Sciences of the United States of America (Online) Journal Issue: 14 Vol. 112; ISSN 1091-6490
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (9)

Proteasome Substrate Capture and Gate Activation by Mycobacterium tuberculosis PafE posted_content January 2018
AAA+ Machines of Protein Destruction in Mycobacteria journal July 2017
Highlighting the Proteasome: Using Fluorescence to Visualize Proteasome Activity and Distribution journal March 2019
The Bacterial Proteasome at the Core of Diverse Degradation Pathways text January 2019
Cdc48-like protein of actinobacteria (Cpa) is a novel proteasome interactor in mycobacteria and related organisms journal May 2018
Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis journal March 2016
Regulation of heat-shock genes in bacteria: from signal sensing to gene expression output journal April 2017
Bacterial Proteasomes: Mechanistic and Functional Insights journal December 2016
Cdc48-like protein of actinobacteria (Cpa) is a novel proteasome interactor in mycobacteria and related organisms text January 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
activator
degradation
mycobacterium
proteasome
tuberculosis