SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6

Hou, Xia; Zhao, Yanzhi; Zhang, Kezhong; Fang, Deyu; Sun, Fei

doi:10.1016/j.bbrc.2017.10.103

Cited by 12 publications

(8 citation statements)

References 25 publications

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“…In addition to targeting many nuclear proteins for proteasomal degradation, attachment of SUMO molecules to a protein can alter its function. In fact, many of the transcription factors, which accumulate as SUMOylated proteins, are ones whose activities are altered by SUMO1 modification, including ATF6 (50), HSF1 (51), HSF2 (52), SMAD3 (53), SMAD4 (54, 55), and FoxM1 (56), whereas the activities of XBP1 (57) and FoxM1 (58) are altered by linkage to SUMO2/3. However, it is impossible to predict whether the buildup of these transcription factors in association with chromatin and PML-NB leads to an overall increase or decrease of transcription, and even less is known how the activities of other nuclear proteins are affected by their SUMOylation.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies

Sha

Blyszcz

González-Prieto

et al. 2019

Journal of Biological Chemistry

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Protein ubiquitination and SUMOylation are required for the maintenance of cellular protein homeostasis, and both increase in proteotoxic conditions (e.g. heat shock or proteasome inhibition). However, we found that when ubiquitination was blocked in several human cell lines by inhibiting the ubiquitin-activating enzyme with TAK243, there was an unexpected, large accumulation of proteins modified by SUMO2/3 chains or SUMO1, but not by several other ubiquitin-like proteins. This buildup of SUMOylated proteins was evident within 3–4 h. It required the small ubiquitin-like modifier (SUMO)-conjugating enzyme, UBC9, and the promyelocytic leukemia protein (PML) and thus was not due to nonspecific SUMO conjugation by ubiquitination enzymes. The SUMOylated proteins accumulated predominantly bound to chromatin and were localized to PML nuclear bodies. Because blocking protein synthesis with cycloheximide prevented the buildup of SUMOylated proteins, they appeared to be newly-synthesized proteins. The proteins SUMOylated after inhibition of ubiquitination were purified and analyzed by MS. In HeLa and U2OS cells, there was a cycloheximide-sensitive increase in a similar set of SUMOylated proteins (including transcription factors and proteins involved in DNA damage repair). Surprisingly, the inhibition of ubiquitination also caused a cycloheximide-sensitive decrease in a distinct set of SUMOylated proteins (including proteins for chromosome modification and mRNA splicing). More than 80% of the SUMOylated proteins whose levels rose or fell upon inhibiting ubiquitination inhibition underwent similar cycloheximide-sensitive increases or decreases upon proteasome inhibition. Thus, when nuclear substrates of the ubiquitin–proteasome pathway are not efficiently degraded, many become SUMO-modified and accumulate in PML bodies.

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Section: Discussionmentioning

confidence: 99%

Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies

Sha

Blyszcz

González-Prieto

et al. 2019

Journal of Biological Chemistry

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“…Thus, post-translational modifications may regulate UPR signalling independent of protein expression and may warrant further investigation in lung cancer and other conditions. 89 90 …”

Section: The Upr and Lung Cancermentioning

confidence: 99%

Role of unfolded proteins in lung disease

Bradley

Stokes

Marciniak

et al. 2020

Thorax

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The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.

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“…Interestingly, this subunit was also required for the transcriptional activity of VP16, suggesting that, at least for VP16, ubiquitylation is a requirement for its transcriptional activity, and is not a consequence of its transcriptional activation [45]. ATF6α has also been shown to be post-translationally modified in other ways, such as glycosylation [46] and SUMOylation [47], and it is certainly true that many post-translational modifications, including ubiquitylation, have been reported to be essential regulators of other transcription factors [48]. Meanwhile, there are varying reports concerning whether nuclear proteasomes are functional and whether ubiquitylated nuclear proteins, potentially including ATF6α, are degraded in the nucleus, or whether they are first transported back to the cytosol [49][50][51].…”

Section: Atf6α Transcriptional Activity and Degradationmentioning

confidence: 99%

Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6α

Stauffer

Arrieta

Blackwood

et al. 2020

IJMS

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There are more than 2000 transcription factors in eukaryotes, many of which are subject to complex mechanisms fine-tuning their activity and their transcriptional programs to meet the vast array of conditions under which cells must adapt to thrive and survive. For example, conditions that impair protein folding in the endoplasmic reticulum (ER), sometimes called ER stress, elicit the relocation of the ER-transmembrane protein, activating transcription factor 6α (ATF6α), to the Golgi, where it is proteolytically cleaved. This generates a fragment of ATF6α that translocates to the nucleus, where it regulates numerous genes that restore ER protein-folding capacity but is degraded soon after. Thus, upon ER stress, ATF6α is converted from a stable, transmembrane protein, to a rapidly degraded, nuclear protein that is a potent transcription factor. This review focuses on the molecular mechanisms governing ATF6α location, activity, and stability, as well as the transcriptional programs ATF6α regulates, whether canonical genes that restore ER protein-folding or unexpected, non-canonical genes affecting cellular functions beyond the ER. Moreover, we will review fascinating roles for an ATF6α isoform, ATF6β, which has a similar mode of activation but, unlike ATF6α, is a long-lived, weak transcription factor that may moderate the genetic effects of ATF6α.

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SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6

Cited by 12 publications

References 25 publications

Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies

Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies

Role of unfolded proteins in lung disease

Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6α

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