Identification of substrates of the Mycobacterium tuberculosis proteasome

The EMBO Journal
Michael J PearceK Heran Darwin

Abstract

The putative proteasome-associated proteins Mpa (Mycobaterium proteasomal ATPase) and PafA (proteasome accessory factor A) of the human pathogen Mycobacterium tuberculosis (Mtb) are essential for virulence and resistance to nitric oxide. However, a direct link between the proteasome protease and Mpa or PafA has never been demonstrated. Furthermore, protein degradation by bacterial proteasomes in vitro has not been accomplished, possibly due to the failure to find natural degradation substrates or other necessary proteasome co-factors. In this work, we identify the first bacterial proteasome substrates, malonyl Co-A acyl carrier protein transacylase and ketopantoate hydroxymethyltransferase, enzymes that are required for the biosynthesis of fatty acids and polyketides that are essential for the pathogenesis of Mtb. Maintenance of the physiological levels of these enzymes required Mpa and PafA in addition to proteasome protease activity. Mpa levels were also regulated in a proteasome-dependent manner. Finally, we found that a conserved tyrosine of Mpa was essential for function. Thus, these results suggest that Mpa, PafA, and the Mtb proteasome degrade bacterial proteins that are important for virulence in mice.

References

Jun 6, 1991·Nature·C K StoverG F Hatfull
Jan 1, 1997·Annual Review of Immunology·J D MacMickingCarl Nathan
May 13, 1997·Proceedings of the National Academy of Sciences of the United States of America·J D MacMickingCarl Nathan
Mar 14, 1998·Molecular Biology of the Cell·F MadeoK U Fröhlich
Feb 26, 1998·Cell·Wolfgang BaumeisterErika Seemüller
Apr 29, 1998·Journal of Molecular Biology·S WolfWolfgang Baumeister
May 1, 1999·Antimicrobial Agents and Chemotherapy·B PhetsuksiriP J Brennan
Mar 11, 2000·European Journal of Biochemistry·O ScholzM Niederweis
Apr 11, 2001·Biochimie·A KöhlerD Finley
May 22, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·L G BekkerG Kaplan
Aug 22, 2001·Chemistry & Biology·A F Kisselev, Alfred L Goldberg
Nov 20, 2001·American Journal of Respiratory Cell and Molecular Biology·E D ChanN W Schluger
May 16, 2002·The Journal of Biological Chemistry·Ihn Sik SeongChin Ha Chung
May 17, 2002·Structure·Masaki UnnoTomitake Tsukihara
May 2, 2003·Proceedings of the National Academy of Sciences of the United States of America·Scott E ConverseJeffery S Cox
Aug 15, 2003·Proceedings of the National Academy of Sciences of the United States of America·Rhoda J KinsellaJames O McInerney
Sep 25, 2003·Neuropsychobiology·Michel HansenneMarc Ansseau
Oct 23, 2003·Annual Review of Cell and Developmental Biology·Susan Gottesman
Mar 3, 2004·Nature Reviews. Molecular Cell Biology·Cecile M Pickart, Robert E Cohen
Jan 22, 2005·Molecular Microbiology·K Heran DarwinCarl Nathan
Apr 25, 2006·Molecular Microbiology·Susan M ButlerK Heran Darwin

Citations

Jun 2, 2009·Nature Reviews. Microbiology·K Heran Darwin
Jul 18, 2009·Nature Reviews. Microbiology·Janine KirsteinKürşad Turgay
May 19, 2009·Nature Structural & Molecular Biology·Frank StriebelEilika Weber-Ban
Jan 3, 2012·The Journal of Biological Chemistry·Cyrille L DelleyEilika Weber-Ban
Nov 26, 2008·The Journal of Biological Chemistry·Kristin E BurnsClifton E Barry
Feb 6, 2007·Journal of Bacteriology·Richard A FestaK Heran Darwin
Mar 14, 2009·Annual Review of Pharmacology and Toxicology·Liem Nguyen, Jean Pieters
May 7, 2013·Future Microbiology·David M RobertsTanya Parish
Jul 6, 2014·Annual Review of Microbiology·Julie A Maupin-Furlow
Apr 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jordan B JastrabK Heran Darwin
Mar 14, 2009·Trends in Biochemical Sciences·George N DeMartino
Nov 15, 2008·Science·Sohini Mukherjee, Kim Orth
Nov 27, 2015·Journal of Molecular Biology·Dominik Barthelme, Robert T Sauer
Jun 26, 2007·Trends in Microbiology·R De Mot
Mar 25, 2015·Scientific Reports·Jacqueline D CobbertAlexander Shekhtman
Jul 9, 2011·EMBO Reports·Francisca A Cerda-MairaK Heran Darwin
Dec 21, 2010·Molecular Microbiology·Richard A FestaK Heran Darwin
Feb 26, 2011·Immunological Reviews·David G Russell
Aug 28, 2010·EMBO Reports·Frank ImkampEilika Weber-Ban
Dec 23, 2009·Molecular Microbiology·Frank ImkampEilika Weber-Ban
Jan 30, 2010·Cellular Microbiology·Kristin E Burns, K Heran Darwin
Apr 6, 2013·Biochimica Et Biophysica Acta·Frank StriebelEilika Weber-Ban
Jul 8, 2009·The Biochemical Journal·Shanhui LiaoXiaoming Tu
Jun 11, 2008·Cell Host & Microbe·Jean Pieters
Oct 22, 2015·Annual Review of Microbiology·Jordan B Jastrab, K Heran Darwin
Apr 2, 2010·Journal of the American Chemical Society·Markus SutterEilika Weber-Ban
Oct 13, 2011·Journal of Proteome Research·M Carolina MehaffyKaren M Dobos
Mar 10, 2016·PloS One·Xuejie ChenJunjie Zhang
Oct 27, 2017·Scientific Reports·Begonia Fudrini OlivenciaFrank Imkamp

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