Ubiquitin-Like Protein Involved in the Proteasome Pathway of
            <i>Mycobacterium tuberculosis</i>

Pearce, Michael J.; Mintseris, Julian; Ferreyra, Jessica A.; Gygi, Steven P.; Darwin, K. Heran

doi:10.1126/science.1163885

Cited by 342 publications

(564 citation statements)

References 22 publications

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“…The conjugation reaction consists of two steps: First, Dop (deamidase of Pup) deamidates the C-terminal glutamine of Pup, converting its C-terminus from GGQ to GGE [15]. This renders Pup competent for conjugation to substrates by the Pup-ligase PafA [15], the function of which had also been predicted by the absence of pupylated substrates in a pafA-knockout strain [14] and bioinformatic analysis [16]. Interestingly, in many organisms the Pup protein ends with GGE ( Fig.…”

Section: Introductionmentioning

confidence: 99%

A distinct structural region of the prokaryotic ubiquitin‐like protein (Pup) is recognized by the N‐terminal domain of the proteasomal ATPase Mpa

et al. 2009

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Edited by Miguel De la RosaKeywords: Prokaryotic ubiquitin-like protein Mpa ARC Proteasome NMR Mycobacterium tuberculosis a b s t r a c tThe mycobacterial ubiquitin-like protein Pup is coupled to proteins, thereby rendering them as substrates for proteasome-mediated degradation. The Pup-tagged proteins are recruited by the proteasomal ATPase Mpa (also called ARC). Using a combination of biochemical and NMR methods, we characterize the structural determinants of Pup and its interaction with Mpa, demonstrating that Pup adopts a range of extended conformations with a short helical stretch in its C-terminal portion. We show that the N-terminal coiled-coil domain of Mpa makes extensive contacts along the central region of Pup leaving its N-terminus unconstrained and available for other functional interactions. Structured summary:MINT-7262427: pup (uniprotkb:B6DAC1) binds (MI:0407) to mpa (uniprotkb:Q0G9Y7) by pull down (MI:0096) MINT-7262440: mpa (uniprotkb:Q0G9Y7) and pup (uniprotkb:B6DAC1) bind (MI:0407) by isothermal titration calorimetry (MI:0065)

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Section: Introductionmentioning

confidence: 99%

A distinct structural region of the prokaryotic ubiquitin‐like protein (Pup) is recognized by the N‐terminal domain of the proteasomal ATPase Mpa

et al. 2009

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“…153 Although Mtb encodes a structurally ubiquitin-like protein called RpfB and even possesses a prokaryotic ubiquitin-like protein system (Pup system) that is functionally analogous to the prototypical ubiquitin system, thus far no direct evidence has demonstrated the capacity of Mtb to resist host immune elimination by utilizing its ubiquitin-like degradation system. 154,155 This is likely because the highly unstructured Pup is unable to act as a post-translational modification or to mediate signaling pathways. Therefore, Mtb inevitably resorts to other tactics to disturb the host immune system.…”

Section: Mycobacterium Tuberculosismentioning

confidence: 99%

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

Chai

Liu

2016

Cell Mol Immunol

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The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.

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“…In this pathway, Pup binds to the target protein to be degraded in a manner similar to that of eukaryotic ubiquitin (47). Pup is activated by the enzyme deamidase of Pup (Dop, Rv2112c), which deamidates the C-terminal glutamine of Pup to form glutamate.…”

Section: Validation Of Quantitative Proteomic Data By Qpcr-tomentioning

confidence: 99%

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Gopinath

Raghunandanan

Gomez

et al. 2015

Molecular & Cellular Proteomics

114

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Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and then reactivate later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well-studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating the virulent laboratory strain of M. tuberculosis that was made dormant employing Wayne's dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free onedimensional LC/MS/MS analysis. The proteome of dormant bacteria was analyzed at nonreplicating persistent stage 1 (NRP1) and stage 2 (NRP2), whereas that of reactivated bacteria was analyzed at 6 and 24 h post reaeration. Proteome of normoxially grown bacteria served as the reference. In total, 1871 proteins comprising 47% of the M. tuberculosis proteome were identified, and many of them were observed to be expressed differentially or uniquely during dormancy and reactivation. The number of proteins detected at different stages of dormancy (764 at NRP1, 691 at NRP2) and reactivation (768 at R6 and 983 at R24) was very low compared with that of the control (1663). The number of unique proteins identified during normoxia, NRP1, NRP2, R6, and R24 were 597, 66, 56, 73, and 94, respectively. We analyzed various biological functions during these conditions. Fluctuation in the relative quantities of proteins involved in energy metabolism during dormancy and reactivation was the most significant observation we made in this study. Proteins that are up-regulated or uniquely expressed during reactivation from dormancy offer to be attractive targets for therapeutic intervention to

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Ubiquitin-Like Protein Involved in the Proteasome Pathway of Mycobacterium tuberculosis

Abstract: The protein modifier ubiquitin is a signal for proteasome-mediated degradation in eukaryotes.

Cited by 342 publications

References 22 publications

A distinct structural region of the prokaryotic ubiquitin‐like protein (Pup) is recognized by the N‐terminal domain of the proteasomal ATPase Mpa

A distinct structural region of the prokaryotic ubiquitin‐like protein (Pup) is recognized by the N‐terminal domain of the proteasomal ATPase Mpa

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

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