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.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016;
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Jastrab
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973;
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Murphy
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973;
authors.forename: Lin
authors.initials: L
authors.lastname: Bai
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794;
authors.forename: Kuan
authors.initials: K
authors.lastname: Hu
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
authors.forename: Remco
authors.initials: R
authors.lastname: Merkx
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195.
authors.forename: Jessica
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195.
authors.forename: Champak
authors.initials: C
authors.lastname: Chatterjee
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794;
authors.forename: Huilin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016; heran.darwin@med.nyu.edu.
authors.forename: K Heran
authors.initials: KH
authors.lastname: Darwin
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006358:Hot Temperature; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity; D010455:Peptides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D014376:Tuberculosis / Q000382:microbiology; D025801:Ubiquitin / Q000737:chemistry; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D006360:Heat-Shock Proteins; D010455:Peptides; D011994:Recombinant Proteins; D025801:Ubiquitin; D012313:RNA; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex
keywords: activator; degradation; mycobacterium; proteasome; tuberculosis
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