Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: New therapeutic targets

Santos‐Laso, Álvaro; Izquierdo-Sánchez, Laura; Rodrigues, Pedro M.; Huang, Bing; Azkargorta, Mikel; Lapitz, Ainhoa; Munoz‐Garrido, Patricia; Arbelaiz, Ander; Caballero-Camino, Francisco J.; Fernández‐Barrena, Maite G.; Jiménez-Agüero, Raúl; Argemí, Josepmaria; Aragón, Tomás; Elortza, Félix; Marzioni, Marco; Drenth, Joost P.H.; LaRusso, Nicholas F.; Bujanda, Luís; Perugorria, María J.; Bañales, Jesús M.

doi:10.1111/liv.14485

Cited by 22 publications

(30 citation statements)

References 41 publications

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“…Based on the identification of increased PSMC2 SUMOylation levels in PHCs and the previously described proteasome hyperactivity of PHCs vs. NHCs 4 - together with the baseline increase of ubiquitinated proteins and p62 (marker of autophagy) expression in cystic tissue from PLD patients and PCK rats compared to controls ( Fig. S6A – D ) - we evaluated the impact of SAMe on proteasome activity.…”

Section: Resultsmentioning

confidence: 99%

“… 16 Indeed, as a result of the mutated genes in PLD, misfolded proteins accumulate in the ER, thereby inducing prolonged ER stress and subsequently UPR hyperactivity. 4 This suggests that enhanced protein SUMOylation in PLD could be related with the UPR, driving disease progression.…”

Section: Discussionmentioning

confidence: 99%

“… 3 Consequently, these gene mutations provoke global abnormalities in both cellular protein homeostasis ( i.e., proteostasis) and function of the protein products, resulting in ER stress and the activation of pro-survival mechanisms. 4 Taken this knowledge into account, we hypothesized that cystic cholangiocytes might be characterized by abnormal protein dynamics linked to adaptive post-translational modification (PTM) processes, leading to the promotion of hepatic cystogenesis. Among the different PTMs, protein SUMOylation has drawn increasing attention as it is an essential and reversible process, governing a plethora of cellular actions such as gene transcription, protein stability, nucleo-cytoplasmic trafficking, cell cycle regulation, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models

Lee

Olaizola

Caballero-Camino

et al. 2021

Journal of Hepatology

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Background & Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Herein, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. Methods: Levels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. Results: Most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdhl -mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUM01-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered proteasome hyperactivity in cystic cholangiocytes, leading to activation of the unfolded protein response and stress-related apoptosis. Conclusions: Cystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models

Lee

Olaizola

Caballero-Camino

et al. 2021

Journal of Hepatology

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“…Abnormal glycosylation has been widely regarded as an important sign of cancer and is significantly associated with tumor development, progression, metastasis, and chemoresistance ( Liu et al, 2018 ; Liu T. et al, 2020a ). As an effective glycosylation inhibitor, tunicamycin has been initially identified as a natural antibiotic and anticancer compound ( Liu Y. C. et al, 2020b ; Santos-Laso et al, 2020 ). Wu et al (2018) have suggested that tunicamycin inhibits N -glycosylation to aggravate ER stress, induces autophagy, and increases the sensitivity of gastric cancer cells to ADM and VCR.…”

Section: Modulatory Effects Of Autophagy Inhibitors and Activators Onmentioning

confidence: 99%

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Tang

et al. 2020

Front. Cell Dev. Biol.

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Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

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“…Indeed, strategies aiming at reducing ER stress modify disease burden in experimental models of PLD. 2 Furthermore, perturbations in posttranslational modifications (PTMs), particularly in SUMOylation, result in aberrant protein dynamics contributing to the pathology. 3 There is elevated protein SUMOylation in cystic cholangiocytes, which drives hepatic cystogenesis in experimental models.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NAE‐dependent protein hyper‐NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease

et al. 2021

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Background Polycystic liver diseases (PLDs) are genetic inherited disorders characterized by the progressive growth of numerous intrahepatic biliary cysts, which are the main cause of morbidity. Previous studies revealed that cystic cholangiocytes are characterized by endoplasmic reticulum stress and aberrant posttranslational modification (PTM) of proteins, in particular hyper‐SUMOylation, that promote PLD pathobiology. Protein NEDDylation is a newly characterized PTM that modulates a plethora of biological processes and its dysregulation is associated with the development and progression of several human diseases. However, the role of NEDDylation in PLD remains elusive. Objective To explore the role of protein NEDDylation in PLD and its potential therapeutic regulatory value. Methods Levels and functional effects of NEDDylation, including response to Pevonedistat (first‐in‐class selective inhibitor of the NEDDylation E1 enzyme NAE), were assessed in vitro, in vivo, and/or in patients with PLD. NEDDylated protein levels in normal and cystic human cholangiocytes were assessed by immunoprecipitation, and the proteomic profile was further analyzed by mass spectrometry. Results and Conclusion The genes involved in the NEDDylation pathway were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture, compared to controls. Elevated levels of NEDDylated proteins were further confirmed in cystic cholangiocytes in vitro, which diminished under Pevonedistat incubation. Pevonedistat promoted apoptotic cell death and reduced proliferation in cystic cholangiocytes in vitro. Comparative proteomic profiling of NEDD8‐immunoprecipitated proteins between normal and cystic cholangiocytes in culture reported candidate proteins involved in cystogenesis, mostly associated with protein biogenesis and quality control. All these data indicate that cystic cholangiocytes display increased protein NEDDylation, contributing to cell survival and proliferation, ultimately supporting hepatic cystogenesis. Targeting of protein hyper‐NEDDylation in cystic cholangiocytes inhibits cystogenesis in experimental models, representing a novel therapeutic opportunity in PLD.

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Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: New therapeutic targets

Cited by 22 publications

References 41 publications

Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models

Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Inhibition of NAE‐dependent protein hyper‐NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease

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