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AMPK directly regulates SirT7 phosphorylation and subcellular distribution under starvation. (a) 293T cells transfected with Flag-SirT7 and HA-AMPKα plasmids were treated with or without GD (4 h), followed by immunoprecipitation with FLAG-M2 beads. The precipitated proteins were analysed by western blot using anti-Flag or anti-HA antibody. (b) In vitro phosphorylation of SirT7 by activated AMPKα. GST-SirT7-WT or -153A mutants were expressed in E.coli and purified with GST beads. Activated Flag-AMPKα was precipitated from GD (6 h) treated Flag-AMPKα-overexpressing 293T cells using FLAG-M2 beads and eluted with Flag peptide. GST-SirT7-WT or -153A proteins were incubated with or without Flag-AMPKα in the presence or absence of ATP as indicated. The reaction product was separated by SDS-PAGE and analysed by western blot. (c) Similar in vitro kinase assay was performed as detailed for (b), except that the kinase-dead AMPKα D159A (AMPK-DN) mutant was used. (d) HeLa cells with AMPKα knockdown (AMPKα-Si) or control Si-RNA (Ctrl-Si) were transfected with Flag-SirT7 following GD (12 h) treatment, then immunostained with anti-Flag (red) or anti-UBF (green) antibodies (scale bar, 10 μm). Nuclei were stained with DAPI. (e) HeLa cells with AMPKα knockdown or control Si-RNA were treated with GD (4 h) followed by immunoprecipitation with anti-SirT7 antibody and western blot analysis. AMPK activation was confirmed by its phosphorylation at Thr-172.
Source publication
Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REGγ-proteasome system plays a role in maintaining energy homeostasis and cell survival during energy starvation via repressing rDNA transcription, a major intracellular energy-consuming process. Mechanistically, REGγ-proteasome...
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Citations
... Autophagy is a cellular self-degradation process that plays a critical role in maintaining cellular homeostasis, clearing abnormal proteins and organelles, and responding to environmental stress [57]. Autophagy involves the sequestration of specific cellular components into double-membrane vesicles called autophagosomes, which are then delivered to lysosomes for degradation and recycling [58]. Key regulatory factors in the process of autophagy include autophagy-related genes (ATGs) and signaling pathways such as mTOR (mammalian target of rapamycin) and AMPK (5'-AMP-activated protein kinase) [59]. ...
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... Furthermore, in pancreatic cancer, PSME3 targets the cellular myelocytomatosis oncogene (c-Myc) to stimulate lactate secretion (11). It also regulates tumor biological functions such as tumor angiogenesis, cell senescence or apoptosis, and lipid and energy metabolism (12)(13)(14)(15)(16). For instance, PSME3 participates in angiogenesis by influencing protein kinase (PKA) conversion in the cyclic adenosine monophosphate/PKA signaling pathway (15). ...
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... Localized in the nucleus, SIRT7 is widely expressed in a variety of tissues and functions to deacetylate histones to regulate gene expression epigenetically [8]. Previous studies have also demonstrated that SIRT7 acts as an oncogene or anti-cancer gene in the progression of diverse cancers, regulating cell proliferation and autophagy, and serves as a stress regulator in physiological homeostasis [9][10][11]. For example, SIRT7 promotes the proliferation and androgen-induced autophagy in prostate cancer via the AR signaling [12]. ...
Background
Sirtuin 7 (SIRT7) is an oncogene that promotes tumor progression in various malignancies, however, its role and regulatory mechanism in cervical squamous cell carcinoma (CSCC) is unknown. Herein, we attempted to investigate the functional role and molecular mechanism of SIRT7 underlying CSCC progression.
Methods
SIRT7 expression was evaluated in CSCC cells using various assays. We then used a series of function gain-and-loss experiments to determine the role of SIRT7 in CSCC progression. Furthermore, mechanism experiments were conducted to assess the interaction between SIRT7/USP39/FOXM1 in CSCC cells. Additionally, rescue assays were conducted to explore the regulatory function of USP39/FOXM1 in CSCC cellular processes.
Results
SIRT7 was highly expressed in CSCC patient tissues and cell lines. SIRT7 deficiency showed significant repression on the proliferation, and autophagy of CSCC cells in vitro and tumorigenesis in vivo. Similarly, apoptosis and ROS production in CSCC cells were accelerated after the SIRT7 knockdown. Moreover, SIRT7 and USP39 were found colocalized in the cell nucleus. Interestingly, SIRT7 was revealed to deacetylate USP39 to promote its protein stability in CSCC cells. USP39 protein was also verified to be upregulated in CSCC tissues and cells. USP39 silencing showed suppressive effects on CSCC cell growth. Mechanistically, USP39 was revealed to upregulate SIRT7 by promoting the transcriptional activity of FOXM1. Rescue assays also indicated that SIRT7 promoted autophagy and inhibited ROS production in CSCC cells by regulating USP39/FOXM1.
Conclusion
The SIRT7/USP39/FOXM1 positive feedback network regulates autophagy and oxidative stress in CSCC, thus providing a new direction for CSCC-targeted therapy.
Graphical Abstract
... This article summarized the research progress of biological behavior of E3 ubiquitin ligase in human placental trophoblast cells in recent years, aiming to provide a strong scientific basis for further exploring the molecular mechanism, target and regulatory mechanism of pregnancy complications. The study on the role of CUL1 in trophoblast differentiation during placental development is still in its infancy (2,5,7). Immunohistochemistry confirmed the expression of CUL1 in CTB cells and EVT of human placenta in early pregnancy. ...
E3 ubiquitin ligases are important components of the ubiquitin protease system. This family includes many proteins, which can catalyze the ubiquitination of a variety of protein substrates and promote the degradation of them by the proteasome system. Recent studies have shown that E3 ubiquitin ligase plays a key role in the process of fetal development and placental formation. It affects the biological behavior of placental trophoblast cells, leading to a series of pregnancy complications that threaten mothers and babies greatly. This review focuses on the regulation, target and mechanism of E3 ubiquitin ligase on the biological behavior of human placental trophoblast cells.
... Moreover, REGγ facilitates the turnover of tumor suppressor p53 by facilitating MDM2-mediated p53 ubiquitination [36] and p53 cellular distribution regulation [37]. Furthermore, REGγ plays roles in the control of a variety of physiological and pathological processes, including cancer progression [38][39][40], energy metabolism [41,42], bacterial infection [43], innate immunity, and inflammatory diseases [44,45]. Previous work shows REGγ mediates regulation of aging through CK1-Mdm2-p53 pathway [46]. ...
Increased accumulation of reactive oxygen species (ROS) and decline of adaptive response of antioxidants to oxidative stimuli has been implicated in the aging process. Nuclear factor erythroid 2-related factor 2 (Nrf2) activation is a core event in attenuating oxidative stress-associated aging. The activity is modulated by a more complex regulatory network. In this study, we demonstrate the proteasome activator REGγ function as a new regulator of Nrf2 activity upon oxidative stress in cell aging model induced by hydrogen peroxide (H2O2). REGγ deficiency promotes cell senescence in primary MEF cells after H2O2 treatment. Accordingly, ROS scavenging is accelerated in WT cells but blunted in REGγ lacking cells during 12-hour recovery from a 1-hour H2O2 treatment, indicating long-lasting antioxidant buffering capacity of REGγ. Mechanistically, through GSK-3β inhibition, REGγ enhances the nuclear distribution and transcriptional activity of Nrf2, which is surveyed by induction of phase II enzymes including Ho1 and Nqo1. Meanwhile, Nrf2 mediates the transcriptional activation of REGγ upon H2O2 stimulation. More interestingly, short-term exposure to H2O2 leads to transiently upregulation and gradually descent of REGγ transcription, however sustained higher REGγ protein level even in the absence of H2O2 for 24 hours. Thus, our results establish a positive feedback loop between REGγ and Nrf2 and a new layer of adaptive response after oxidative stimulation that is the REGγ-GSK-3β-Nrf2 pathway.
... The ubiquitin-proteasome regulatory system controls protein homeostasis of almost the entire proteome [14][15][16]. Ubiquitin-mediated proteolysis primarily consists E1 activating enzymes, E2 conjugating enzymes, and E3 ubiquitin ligases. Accumulating evidences have found that E3 ligases of both the RING and the HECT family regulate EMT process via ubiquitination, including βTrCP, Skp2, Fbw7, and Cullin 7/Fbxw8 [17][18][19][20][21]. Tripartite motif proteins (TRIMs) belong to the family of E3 ubiquitin ligases. ...
Background:
Currently, how to successfully control refractory and metastatic diseases remains a fundamental goal for clinicians to improve therapeutic effects for patients with non-small cell lung cancer (NSCLC). Several studies have discovered that TRIM58, a member of tripartite motif protein family, shows antitumor effect in multiple types of cancer. In this study, we aimed to further clarify the molecular regulatory network of TRIM58 and corresponding targets for NSCLC patients.
Methods:
TRIM58 expression in clinical tumor tissue samples and cancer cell lines was examined. Functional experiments including cellular invasion, cell metastasis, chemoresistance assay, and ubiquitination evaluation experiments were conducted to investigate the interaction between TRIM58 and ZEB1, which is a prime element of transcription factor network that controls epithelial-to-mesenchymal transition.
Results:
TRIM58 expression was characteristically decreased in NSCLC tumor tissues and cancer cell lines. Functional experiments demonstrated that TRIM58 suppression enhanced malignant biological behaviors including cellular survivability, migration, and invasion, as well as stem-like cellular phenotype of tumor cells. TRIM58 silencing also significantly enhanced the chemoresistance of NSCLC cells to chemoagents. TRIM58-ZEB1 interaction accelerated degradation of ZEB1 protein, thus further leading to the augment of tumor behaviors. Further detailed molecular experiments revealed that the interaction between TRIM58 and ZEB1 was mediated via ubiquitin-proteasome pathway (UPP).
Conclusion:
TRIM58 suppressed NSCLC through interacting with ZEB1 and promoting ZEB1 protein degradation via UPP. The present research sheds light on the interaction between TRIM58 and ZEB1, and TRIM58/ZEB1 axis might be the potential therapeutic targets of NSCLC.
... And Psme3 gene transfer improves motor coordination in mouse model of Huntington's disease [70]. This gene is involved in the pathways of amino acid and derivative metabolism (R-HSA-71291), ABC-family proteins-mediated transport (R-HSA-382556), APC/C-mediated degradation of cell cycle proteins (R-HSA-174143), and is reported to regulate energy homeostasis [71]. Our data suggest that a novel type of targets involving nodes of the important pathways modulating protein synthesis, energy production, and neurotransmission (BCAAs) simultaneously, might better explain some severe problems in ASD, such as comorbidity with ID and language impairment. ...
Background
Autism spectrum disorder (ASD) is often accompanied by intellectual disability (ID). Despite extensive studies, however, the genetic basis for this comorbidity is still not clear. In this study, we tried to develop an analyzing pipeline for de novo mutations and possible pathways related to ID phenotype in ASD. Whole-exome sequencing (WES) was performed to screen de novo mutations and candidate genes in 79 ASD children together with their parents (trios). The de novo altering genes and relative pathways which were associated with ID phenotype were analyzed. The connection nodes (genes) of above pathways were selected, and the diagnostic value of these selected genes for ID phenotype in the study population was also evaluated.
Results
We identified 89 de novo mutant genes, of which 34 genes were previously reported to be associated with ASD, including double hits in the EGF repeats of NOTCH1 gene (p.V999M and p.S1027L). Interestingly, of these 34 genes, 22 may directly affect intelligence quotient (IQ). Further analyses revealed that these IQ-related genes were enriched in protein synthesis, energy metabolism, and amino acid metabolism, and at least 9 genes (CACNA1A, ALG9, PALM2, MGAT4A, PCK2, PLEKHA1, PSME3, ADI1, and TLE3) were involved in all these three pathways. Seven patients who harbored these gene mutations showed a high prevalence of a low IQ score (< 70), a non-verbal language, and an early diagnostic age (< 4 years). Furthermore, our panel of these 9 genes reached a 10.2% diagnostic rate (5/49) in early diagnostic patients with a low IQ score and also reached a 10% diagnostic yield in those with both a low IQ score and non-verbal language (4/40).
Conclusion
We found some new genetic disposition for ASD accompanied with intellectual disability in this study. Our results may be helpful for etiologic research and early diagnoses of intellectual disability in ASD. Larger population studies and further mechanism studies are warranted.
... A previous study showed that SIRT7 is phosphorylated by the cyclindependent kinase 1 (CDK1)-cyclin B pathway during mitosis [19]. Another study demonstrated that AMPK phosphorylates SIRT7 under energy stress, and SIRT7 is modified by ubiquitination [20]. However, the deubiquitination process that regulates the protein level of SIRT7 in cancers remains unclear. ...
Purpose
Sirtuin7 (SIRT7), as a member of the sirtuin and NAD⁺-dependent protein-modifying enzyme family, plays an important role in regulating cellular metabolism, stress responses, tumorigenesis, and aging. Ubiquitination and deubiquitination are reversible post-translational modifications that regulate protein stability, enzyme activity, protein–protein interactions, and cellular signaling transduction. However, whether SIRT7 is regulated by deubiquitination signaling is unclear. This study aims to elucidate the molecular mechanism of SIRT7 via deubiquitination signaling.
Methods
USP17L2 or SIRT7-targeting shRNAs were used to deplete USP17L2 or SIRT7. Western blot was applied to assess the effects of USP17L2 or SIRT7 depletion. A co-immunoprecipitation assay was used to detect the interaction relationship. Cell Counting Kit-8 assays were applied to assess the viability of breast cancer cells. An immunohistochemistry assay was employed to detect the protein level in samples from breast cancer patients, and the TCGA database was applied to analyze the survival rate of breast cancer patients. Statistical analyses were performed with the Student’s t test (two-tailed unpaired) and χ² test.
Results
We find that the deubiquitinase USP17L2 interacts with and deubiquitinates SIRT7, thereby increasing SIRT7 protein stability. In addition, USP17L2 regulates DNA damage repair through SIRT7. Furthermore, SIRT7 polyubiquitination is increased by knocking down of USP17L2, which leads to cancer cells sensitizing to chemotherapy. In breast cancer patient samples, high expression of USP17L2 is correlated with increased levels of SIRT7 protein. In conclusion, our study demonstrates that the USP17L2-SIRT7 axis is the new regulator in DNA damage response and chemo-response, suggesting that USP17L2 may be a prognostic factor and a potential therapeutic target in breast cancer.
Conclusion
Our results highlighted that USP17L2 regulates the chemoresistance of breast cancer cells in a SIRT7-dependent manner. Moreover, the role of USP17L2 as a potential therapeutic target in breast cancer and a prognostic factor for patients was elucidated.
... In eukaryotes, PA28γ has a variety of PTM processes. For example, mutants of amino acids at different SUMO sites of PA28γ can be constructed, which can make PA28γ chemotactic to the cytoplasm and ultimately maintain its own protein stability [46,47]. In addition, the yeast two-hybrid experiment showed that MEKK3 can interact with PA28γ. ...
Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4–17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.
... Factors involved immune responses are also found as REGγ targets, including signal transducer and a vator of transcription 3 (Stat3) [14], activation-induced deaminase (AID) [18], interfe regulatory factor 8 (IRF8) [19], and Oct-1 [20]. Likewise, some key proteins involved metabolism that are also degraded by REGγ include SirT1 [21], SirT7 [22], and prot kinase A (PKA) [23]. Intriguingly, additional REGγ targets include factors involved neurodegenerative diseases such as tauopathies or Alzheimer's disease, and the decl of REGγ was shown to be associated with the acceleration of aging-related brain disord [24]. ...
... To do so, the REGγ-proteasome targets SirT7, an rDNA transcriptional activator, for degradation. Importantly, researchers also found that REGγ deficiency sensitized cells to starvation-induced apoptosis under glucose-deprived conditions in a manner not dependent on p53, indicating REGγ inhibition as a potential strategy for tumor-starving cancer therapies [22]. Hence, REGγ helps to maintain cellular energy levels in multiple cellular contexts and regulates signaling involved in energy metabolism. ...
REGγ, a proteasome activator belonging to the 11S (otherwise known as REG, PA28, or PSME) proteasome activator family, is widely present in many eukaryotes. By binding to the 20S catalytic core particle, REGγ acts as a molecular sieve to selectively target proteins for degradation in an ATP- and ubiquitin-independent manner. This non-canonical proteasome pathway directly regulates seemingly unrelated cellular processes including cell growth and proliferation, apoptosis, DNA damage response, immune response, and metabolism. By affecting different pathways, REGγ plays a vital role in the regulation of cellular life and death through the maintenance of protein homeostasis. As a promoter of cellular growth and a key regulator of several tumor suppressors, many recent studies have linked REGγ overexpression with tumor formation and suggested the REGγ-proteasome as a potential target of new cancer-drug development. This review will present an overview of the major functions of REGγ as it relates to the regulation of cellular life and death, along with new mechanistic insights into the regulation of REGγ.
