UBC9 Regulates the Stability of XBP1, a Key Transcription Factor Controlling the ER Stress Response

Uemura, Aya; Taniguchi, Masaru; Matsuo, Yuko; Oku, Masaya; Wakabayashi, Shigeo; Yoshida, Hiderou

doi:10.1247/csf.12026

Cited by 27 publications

(23 citation statements)

References 45 publications

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“…Recent studies suggest that UBC9 may also impact on ER homeostasis; for example UBC9 protein regulates the expression of XBP-1 and the transcript's stability. 36 We confirmed that components of the UPR, including XBP-1, are upregulated by elevated levels of UBC9 (Online Figure VII) and UBC9 can directly target promoter elements involved in UPR activation (Online Figure VIIC and D). …”

Section: Resultssupporting

confidence: 68%

Sumo E2 Enzyme UBC9 Is Required for Efficient Protein Quality Control in Cardiomyocytes

Gupta

Gulick

Liu

et al. 2014

Circulation Research

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Rationale Impairment of proteasomal function is pathogenic in a number of cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation and, while the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control (PQC) is not fully understood. Objective To determine the role of UBC9, a SUMO-conjugating enzyme, in cardiomyocyte PQC. Methods and Results Gain- and loss-of-function approaches were used to determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function in cardiomyocytes while knockdown of UBC9 by siRNA caused significant accumulations of aggregated protein. UPS function and relative activity was analyzed using a UPS reporter protein, GFPu. Subsequently, UBC9's effects on UPS function were tested in a proteotoxic model of desmin-related cardiomyopathy, caused by cardiomyocyte specific expression of a mutated alpha B crystallin, CryABR120G. CryABR120G expression leads to aggregate formation and decreased proteasomal function. Co-infection of UBC9-adenovirus with CryABR120G virus reduced the proteotoxic sequelae, decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 significantly decreased UPS function in the model and resulted in increased aggregate levels. Conclusions UBC9 plays a significant role in cardiomyocyte PQC and its activity can be exploited to reduce toxic levels of misfolded or aggregated proteins in cardiomyopathy.

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Section: Resultssupporting

confidence: 68%

Sumo E2 Enzyme UBC9 Is Required for Efficient Protein Quality Control in Cardiomyocytes

Gupta

Gulick

Liu

et al. 2014

Circulation Research

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“…From an evolutionary perspective, proteins such as Ubc-9 are suitable targets for pathogens because of their multifunctional role. These proteins, in addition to their E2 enzyme activity, could potentially function as biological chaperones, transcriptional coregulators, and regulators of signaling pathways (44)(45)(46)(47). The evolutionary conservation of Ubc-9 being at the center of many strategies to subvert host SUMO machinery is also mirrored in our observation regarding the mechanism of Ubc-9 degradation.…”

Section: Discussionsupporting

confidence: 57%

Salmonella Engages Host MicroRNAs To Modulate SUMOylation: a New Arsenal for Intracellular Survival

Verma

Mohapatra

Mustfa

et al. 2015

Molecular and Cellular Biology

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c Posttranslational modifications (PTMs) can alter many fundamental properties of a protein. One or combinations of them have been known to regulate the dynamics of many cellular pathways and consequently regulate all vital processes. Understandably, pathogens have evolved sophisticated strategies to subvert these mechanisms to achieve instantaneous control over host functions. Here, we present the first report of modulation by intestinal pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) of host SUMOylation, a PTM pathway central to all fundamental cellular processes. Both in cell culture and in a mouse model, we observed that S. Typhimurium infection led to a dynamic SUMO-conjugated proteome alteration. The intracellular survival of S. Typhimurium was dependent on SUMO status as revealed by reduced infection and Salmonella-induced filaments (SIFs) in SUMO-upregulated cells. S. Typhimurium-dependent SUMO modulation was seen as a result of depletion of crucial SUMO pathway enzymes Ubc-9 and PIAS1, at both the protein and the transcript levels. Mechanistically, depletion of Ubc-9 relied on upregulation of small noncoding RNAs miR30c and miR30e during S. Typhimurium infection. This was necessary and sufficient for both down-modulation of Ubc-9 and a successful infection. Thus, we demonstrate a novel strategy of pathogen-mediated perturbation of host SUMOylation, an integral mechanism underlying S. Typhimurium infection and intracellular survival.

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“…For example, XBP1(U) protein forms a complex with XBP1(S) protein, and undergoes rapid proteasome degradation under non-stress conditions, which shuts off the transcription of target genes of XBP1(S) during the recovery phase of ER stress [48]. It was also reported that the small ubiquitin-like modifier (SUMO) conjugase ubiquitin-conjugating enzyme 9 (UBC9) specifically binds to XBP1(S) and increases its stability [49]. …”

Section: Unfolded Protein Responses In Mammalsmentioning

confidence: 99%

Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

Ariyasu

Yoshida

Hasegawa

2017

IJMS

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The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article.

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UBC9 Regulates the Stability of XBP1, a Key Transcription Factor Controlling the ER Stress Response

Cited by 27 publications

References 45 publications

Sumo E2 Enzyme UBC9 Is Required for Efficient Protein Quality Control in Cardiomyocytes

Sumo E2 Enzyme UBC9 Is Required for Efficient Protein Quality Control in Cardiomyocytes

Salmonella Engages Host MicroRNAs To Modulate SUMOylation: a New Arsenal for Intracellular Survival

Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

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