Proteomics Reveals Scope of Mycolactone-mediated Sec61 Blockade and Distinctive Stress Signature

Morel, Jean-David; Paatero, Anja O.; Wei, Jiajie; Yewdell, Jonathan W.; Guenin-Macé, Laure; Haver, Delphi Van; Impens, Francis; Pietrosemoli, Natalia; Paavilainen, Ville O.; Demangel, Caroline

doi:10.1074/mcp.ra118.000824

Cited by 60 publications

(136 citation statements)

References 37 publications

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“…Interestingly in this study the translational activation of ATF4 was observed in the absence of an unfolded protein response (UPR) [Ogbechi et al., ] that is indicative of ER stress [Oakes and Papa, ]. In contrast, we observed that DCs display clear hallmarks of ER stress‐specific activation signals within hours of mycolactone treatment [Morel et al., ], consistent with a broad‐ranging blockade of protein translocation [Grotzke et al., ]. However, mycolactone‐driven ER stress in DCs differed from a conventional UPR since there was a down‐regulation of BiP [Morel et al., ], a master regulator of the UPR that is induced by canonical ER stress but that relies on mycolactone‐sensitive, Sec61 dependent, translocation to access the ER lumen ([Baron et al., ], Figure ).…”

Section: Mycolactone‐mediated Sec61 Blockade and Clinical Manifestatimentioning

confidence: 56%

“…In contrast, we observed that DCs display clear hallmarks of ER stress‐specific activation signals within hours of mycolactone treatment [Morel et al., ], consistent with a broad‐ranging blockade of protein translocation [Grotzke et al., ]. However, mycolactone‐driven ER stress in DCs differed from a conventional UPR since there was a down‐regulation of BiP [Morel et al., ], a master regulator of the UPR that is induced by canonical ER stress but that relies on mycolactone‐sensitive, Sec61 dependent, translocation to access the ER lumen ([Baron et al., ], Figure ). In practice, whether mycolactone‐driven ATF4 induction results from the ISR, the UPR, or a combination of these stress responses, may well depend on cell type.…”

Section: Mycolactone‐mediated Sec61 Blockade and Clinical Manifestatimentioning

confidence: 82%

“…Thus, exactly how a nascent precursor protein engages the Sec61 complex (Figure , stage 4) is probably an important factor in determining the effectiveness with which mycolactone blocks its subsequent translocation [McKenna et al., ]. The profiling of mycolactone's signature in the proteomes of CD4 + T lymphocytes, DCs and DRG neurons [Baron et al., ; Grotzke et al., ; Morel et al., ], broadly supports this model for the effects of mycolactone on different classes of single‐spanning membrane proteins ([McKenna et al., ], Figure ). The global effects of mycolactone on the biogenesis of multi‐spanning membrane proteins are more complex, and further cell‐free studies of such substrates should help reveal how they arise from the inhibition of the Sec61 complex.…”

Section: Mycolactone Blocks Protein Translocation At the Endoplasmic mentioning

confidence: 91%

“…In contrast, tail‐anchored (TA) membrane proteins do not require the Sec61 complex for membrane insertion [Johnson et al., ]. The effects of mycolactone on these different classes of proteins, as determined using both cell‐free translation systems (CFT) and cell culture studies [Baron et al., ; Hall et al., ; McKenna et al., , ; Morel et al., ], are summarised above. The N‐terminal signal peptides (SP) found on secretory and Type I membrane proteins are cleaved after the precursor is targeted to the ER.…”

Section: Mycolactone Blocks Protein Translocation At the Endoplasmic mentioning

confidence: 99%

“…Importantly, these global proteomic analyses also highlighted alterations beyond those on the Sec61 substrates detailed above, most‐likely resulting from the cascading effects of the protein translocation blockade [Baron et al., ; Grotzke et al., ; Morel et al., ] and from cellular stress responses that are described below in section Mycolactone‐Mediated Sec61 Blockade and Clinical Manifestations of BU . These effects have particularly important consequences for the immune control of M. ulcerans infection [Baron et al., ; Grotzke et al., ]; and all clinical manifestations of BU (as outlined in section Mycolactone‐Mediated Sec61 Blockade and Clinical Manifestations of BU ).…”

Section: Mycolactone Blocks Protein Translocation At the Endoplasmic mentioning

confidence: 99%

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Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Demangel

High

2018

Biology of the Cell

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Infection with Mycobacterium ulcerans results in a necrotising skin disease known as a Buruli ulcer, the pathology of which is directly linked to the bacterial production of the toxin mycolactone. Recent studies have identified the protein translocation machinery of the endoplasmic reticulum (ER) membrane as the primary cellular target of mycolactone, and shown that the toxin binds to the core subunit of the Sec61 complex. Mycolactone binding strongly inhibits the capacity of the Sec61 translocon to transport newly synthesised membrane and secretory proteins into and across the ER membrane. Since the ER acts as the entry point for the mammalian secretory pathway, and hence regulates initial access to the entire endomembrane system, mycolactone-treated cells have a reduced ability to produce a range of proteins including secretory cytokines and plasma membrane receptors. The global effect of this molecular blockade of protein translocation at the ER is that the host is unable to mount an effective immune response to the underlying mycobacterial infection. Prolonged exposure to mycolactone is normally cytotoxic, since it triggers stress responses activating the transcription factor ATF4 and ultimately inducing apoptosis.

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Section: Mycolactone‐mediated Sec61 Blockade and Clinical Manifestatimentioning

confidence: 56%

Section: Mycolactone‐mediated Sec61 Blockade and Clinical Manifestatimentioning

confidence: 82%

Section: Mycolactone Blocks Protein Translocation At the Endoplasmic mentioning

confidence: 91%

Section: Mycolactone Blocks Protein Translocation At the Endoplasmic mentioning

confidence: 99%

Section: Mycolactone Blocks Protein Translocation At the Endoplasmic mentioning

confidence: 99%

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Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Demangel

High

2018

Biology of the Cell

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Methodologies for Measuring Protein Trafficking across Cellular Membranes

Lyu

Genereux

2021

ChemPlusChem

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Nearly all proteins are synthesized in the cytosol. The majority of this proteome must be trafficked elsewhere, such as to membranes, to subcellular compartments, or outside of the cell. Proper trafficking of nascent protein is necessary for protein folding, maturation, quality control and cellular and organismal health. To better understand cellular biology, molecular and chemical technologies to properly characterize protein trafficking (and mistrafficking) have been developed and applied. Herein, we take a biochemical perspective to review technologies that enable spatial and temporal measurement of protein distribution, focusing on both the most widely adopted methodologies and exciting emerging approaches.

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Biochemical and Biological Assays of Mycolactone-Mediated Inhibition of Sec61

O’Keefe

High

Demangel

2021

Methods in Molecular Biology

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Mycobacterium ulcerans, the causative agent of Buruli ulcer disease, is unique among human pathogens in its capacity to produce mycolactone, a diffusible macrolide with immunosuppressive and cytotoxic properties. Recent studies have shown that mycolactone targets the host membrane translocation complex (Sec61), with an unprecedented potency compared to previously identified Sec61 blockers. Mycolactone binding to the pore-forming subunit of Sec61 inhibits its capacity to transport nascent secretory and membrane proteins into the endoplasmic reticulum, leading to their cytosolic degradation by the ubiquitin:proteasome system. In T lymphocytes, Sec61 blockade by mycolactone manifests as a sharp decrease in the cell's ability to express homing receptors and release cytokines following activation. Sustained exposure of cells to mycolactone typically generates proteotoxic stress responses in their cytosol and ER, ultimately inducing apoptosis. Here we describe cell-free systems for studying Sec61-mediated protein translocation that allow the impact of mycolactone on the biogenesis of secretory and membrane proteins to be probed.We also describe biological assays of mycolactone-driven inhibition of Sec61 providing rapid and sensitive means to quantitatively assess the presence of the toxin in biological samples.

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Proteomics Reveals Scope of Mycolactone-mediated Sec61 Blockade and Distinctive Stress Signature

Cited by 60 publications

References 37 publications

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Methodologies for Measuring Protein Trafficking across Cellular Membranes

Biochemical and Biological Assays of Mycolactone-Mediated Inhibition of Sec61

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