Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Bergmann, Timothy J.; Fregno, Ilaria; Fumagalli, Fiorenza; Rinaldi, Andrea; Bertoni, Francesco; Boersema, Paul J.; Picotti, Paola; Molinari, Maurizio

doi:10.1074/jbc.ra117.001484

Cited by 56 publications

(66 citation statements)

References 69 publications

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“…As such, when studying chemically induced UPR, one must consider that pleiotropic effects are a relevant part of the observed cellular response. Indeed, when looking at transcriptional profiles on treatment with ER stress inducing drugs, the UPR signature is only a minor part of the transcriptional response [Bergmann et al., ]. For example, in a study performed in our lab, we observed that UPR target genes induced upon Tm treatment, at concentrations commonly used in the literature, represented only 19% (97 out of 508 up‐regulated genes) of the total response.…”

Section: Chemically Induced Er Stress: Pleiotropic Effects Full‐blowmentioning

confidence: 73%

Three branches to rule them all? UPR signalling in response to chemically versus misfolded proteins‐induced ER stress

Bergmann

Molinari

2018

Biology of the Cell

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Study of the unfolded protein responses (UPR) is mainly addressed by challenging eukaryotic cells with chemical compounds that impair calcium, redox or glycan homeostasis. These dramatically alter the endoplasmic reticulum (ER) environment and function, but also trigger pleiotropic effects that may result in multi-organellar failure and cell death. Recent works showed that UPR induced by the accumulation of unfolded polypeptides in the ER lumen drastically differs from chemically induced UPR. Unfolded proteins are tolerated by cells, which activate a finely tuned UPR without entering apoptotic programs. How cells adapt the UPR to the burden of misfolded proteins, what structural features of the accumulating proteins determine UPR intensity and how these mechanisms translate into disease are crucial questions to be address in the future.

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Section: Chemically Induced Er Stress: Pleiotropic Effects Full‐blowmentioning

confidence: 73%

Three branches to rule them all? UPR signalling in response to chemically versus misfolded proteins‐induced ER stress

Bergmann

Molinari

2018

Biology of the Cell

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“…When compared to the ~6-fold change (for Tm) observed for Hrd1, however, any responsive contribution made by other E3s to ER stress resolution may be nominal. Of the 226 HCIPs identified, 24 are among the 278 targets of the UPR transcription factors XBP1, ATF6, and ATF4 collated previously 58 , with a quarter (6/24) represented by the Hrd1 complex alone (Extended Data Table 7). Moreover, ER homeostatic 5 maintenance did not require any individual ER-E3 since siRNA-mediated knockdowns of endogenous isoforms were not sufficient to induce the splicing of XBP1 (Extended Data Fig.…”

Section: Er-e3s Erad and Er Stressmentioning

confidence: 99%

Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling

Fenech

Lari

Charles

et al. 2020

Preprint

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Ubiquitin ligases (E3s) embedded in the endoplasmic reticulum (ER) membrane regulate essential cellular activities including protein quality control, calcium flux, and sterol homeostasis. At least 25 different, transmembrane domain (TMD)-containing E3s are predicted to be ER-localised, but for most their organisation and cellular roles remain poorly 5 defined. Using a comparative proteomic workflow, we mapped over 450 protein-protein interactions for 21 different stably expressed, full-length E3s. Bioinformatic analysis linked ER-E3s and their interactors to multiple homeostatic, regulatory, and metabolic pathways. Among these were four membrane-embedded interactors of RNF26, a polytopic E3 whose abundance is auto-regulated by ubiquitin-proteasome dependent degradation. RNF26 co-assembles with 10 TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway. This RNF26 complex represents a new modulatory axis of STING and innate immune signalling at the ER membrane. Collectively, these data reveal the broad scope of regulation and differential functionalities mediated by ER-E3s for both membrane-tethered and cytoplasmic processes. 15

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“…The usual stimuli that have been used to induce IRE1a clustering, such as the glycosylation inhibitor Tm or the reductant DTT, impart severe stress via global proteomic changes that were shown to differ dramatically from expression of a misfolded protein (44). Therefore, we sought to determine if and how milder stresses induce IRE1a clustering.…”

Section: Clustering Of Ire1a Under Mild Er Stressmentioning

confidence: 99%

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity

et al. 2019

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The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades. In addition, the sensor IRE1α exhibits stress‐induced clustering in a transient time frame similar to activation of its endoRNase activity. Previous work had suggested that the clustering response and RNase activity of IRE1α are functionally linked, but here we show that they are independent of each other and have different behaviors and modes of activation. Although both clustering and the RNase activity are responsive to luminal stress conditions and to depletion of the ER chaperone binding protein, RNase‐inactive IRE1α still clusters and, conversely, full RNase activity can be accomplished without clustering. The clusters formed by RNase‐inactive IRE1α are much larger and persist longer than those induced by ER stress. Clustering requires autophosphorylation, and an IRE1α mutant whose RNase domain is responsive to ligands that bind the kinase domain forms yet a third type of stress‐independent cluster, with distinct physical properties and half‐lives. These data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor.—Ricci, D., Marrocco, I., Blumenthal, D., Dibos, M., Eletto, D., Vargas, J., Boyle, S., Iwamoto, Y., Chomistek, S., Paton, J. C., Paton, A. W., Argon, Y. Clustering of IRE1α depends on sensing ER stress but not on its RNase activity. FASEB J. 33, 9811–9827 (2019). http://www.fasebj.org

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Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Cited by 56 publications

References 69 publications

Three branches to rule them all? UPR signalling in response to chemically versus misfolded proteins‐induced ER stress

Three branches to rule them all? UPR signalling in response to chemically versus misfolded proteins‐induced ER stress

Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity

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