Ubiquitination and proteosome-dependent degradation of the activated form of human liver-enriched transcription factor CREB-H regulated by protein kinase A

Poster Presentation - Theme 1: Cell biologyCREB-H is a membrane-bound bZIP transcription factor which is mainly expressed in liver and small intestine. CREB-H plays important roles in the regulation of lipid metabolism, iron metabolism, gluconeogenesis and acute phase response. CREB-H is proteolytically activated by regulated intramembrane proteolysis to generate a C-terminal truncated form known as ...postprin

β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H

CREB-H is an endoplasmic reticulum-resident bZIP transcription factor which critically regulates lipid homeostasis and gluconeogenesis in the liver. CREB-H is proteolytically activated by regulated intramembrane proteolysis to generate a C-terminally truncated form known as CREB-H-ΔTC, which translocates to the nucleus to activate target gene expression. CREB-H-ΔTC is a fast turnover protein but the mechanism governing its destruction was not well understood. In this study, we report on β-TrCP-dependent ubiquitination and proteasomal degradation of CREB-H-ΔTC. The degradation of CREB-H-ΔTC was mediated by lysine 48-linked polyubiquitination and could be inhibited by proteasome inhibitor. CREB-H-ΔTC physically interacted with β-TrCP, a substrate recognition subunit of the SCFβ-TrCP E3 ubiquitin ligase. Forced expression of β-TrCP increased the polyubiquitination and decreased the stability of CREB-H-ΔTC, whereas knockdown of β-TrCP had the opposite effect. An evolutionarily conserved sequence, SDSGIS, was identified in CREB-H-ΔTC, which functioned as the β-TrCP-binding motif. CREB-H-ΔTC lacking this motif was stabilized and resistant to β-TrCP-induced polyubiquitination. This motif was a phosphodegron and its phosphorylation was required for β-TrCP recognition. Furthermore, two inhibitory phosphorylation sites close to the phosphodegron were identified. Taken together, our work revealed a new intracellular signaling pathway that controls ubiquitination and degradation of the active form of CREB-H transcription factor.published_or_final_versio

Association of subclinical myocardial injury with arterial stiffness in patients with type 2 diabetes mellitus

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Predictive value of high-sensitivity troponin-I for future adverse cardiovascular outcome in stable patients with type 2 diabetes mellitus

INTRODUCTION: High-sensitivity cardiac troponin I(hs-TnI) and T levels(hs-TnT) are sensitive biomarkers of cardiomyocyte turnover or necrosis. Prior studies of the predictive role of hs-TnT in type 2 diabetes mellitus(T2DM) patients have yielded conflicting results. This study aimed to determine whether hs-TnI, which is detectable in a higher proportion of normal subjects than hsTnT, is associated with a major adverse cardiovascular event(MACE) in T2DM patients. METHODS AND RESULTS: We compared hs-TnI level in stored serum samples from 276 consecutive patients (mean age 65 +/- 10 years; 57% male) with T2DM with that of 115 age-and sex-matched controls. All T2DM patients were prospectively followed up for at least 4 years for incidence of MACE including heart failure(HF), myocardial infarction(MI) and cardiovascular mortality. At baseline, 274(99%) patients with T2DM had detectable hs-TnI, and 57(21%) had elevated hs-TnI (male: 8.5 ng/L, female: 7.6 ng/L, above the 99th percentile in healthy controls). A total of 43 MACE occurred: HF(n = 18), MI(n = 11) and cardiovascular mortality(n = 14). Kaplan-Meier analysis showed that an elevated hs-TnI was associated with MACE, HF, MI and cardiovascular mortality. Although multivariate analysis revealed that an elevated hs-TnI independently predicted MACE, it had limited sensitivity(62.7%) and positive predictive value(38.5%). Contrary to this, a normal hs-TnI level had an excellent negative predictive value(92.2%) for future MACE in patients with T2DM. CONCLUSION: The present study demonstrates that elevated hs-TnI in patients with T2DM is associated with increased MACE, HF, MI and cardiovascular mortality. Importantly, a normal hs-TnI level has an excellent negative predictive value for future adverse cardiovascular events during long-term follow-up.published_or_final_versio

Requirement of CRTC1 coactivator for hepatitis B virus transcription

Transcription of hepatitis B virus (HBV) from the covalently closed circular DNA (cccDNA) template is essential for its replication. Suppressing the level and transcriptional activity of cccDNA might have anti-HBV effect. Although cellular transcription factors, such as CREB, which mediate HBV transcription, have been well described, transcriptional coactivators that facilitate this process are incompletely understood. In this study we showed that CREB-regulated transcriptional coactivator 1 (CRTC1) is required for HBV transcription and replication. The steady-state levels of CRTC1 protein were elevated in HBV-positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 or its homolog CRTC2 or CRTC3 in hepatoma cells stimulated the activity of the preS2/S promoter of HBV, whereas overexpression of a dominant inactive form of CRTC1 inhibited HBV transcription. CRTC1 interacts with CREB and they are mutually required for the recruitment to the preS2/S promoter on cccDNA and for the activation of HBV transcription. Accumulation of pregenomic RNA (pgRNA) and cccDNA was observed when CRTC1 or its homologs were overexpressed, whereas the levels of pgRNA, cccDNA and secreted HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Our work reveals an essential role of CRTC1 coactivator in facilitating and supporting HBV transcription and replication.published_or_final_versio

Coherent optical wavelength conversion via cavity-optomechanics

We theoretically propose and experimentally demonstrate coherent wavelength conversion of optical photons using photon-phonon translation in a cavity-optomechanical system. For an engineered silicon optomechanical crystal nanocavity supporting a 4 GHz localized phonon mode, optical signals in a 1.5 MHz bandwidth are coherently converted over a 11.2 THz frequency span between one cavity mode at wavelength 1460 nm and a second cavity mode at 1545 nm with a 93% internal (2% external) peak efficiency. The thermal and quantum limiting noise involved in the conversion process is also analyzed, and in terms of an equivalent photon number signal level are found to correspond to an internal noise level of only 6 and 4x10-3 quanta, respectively.Comment: 11 pages, 7 figures, appendi

Zero Sound in Effective Holographic Theories

We investigate zero sound in $D$-dimensional effective holographic theories, whose action is given by Einstein-Maxwell-Dilaton terms. The bulk spacetimes include both zero temperature backgrounds with anisotropic scaling symmetry and their near-extremal counterparts obtained in 1006.2124 [hep-th], while the massless charge carriers are described by probe D-branes. We discuss thermodynamics of the probe D-branes analytically. In particular, we clarify the conditions under which the specific heat is linear in the temperature, which is a characteristic feature of Fermi liquids. We also compute the retarded Green's functions in the limit of low frequency and low momentum and find quasi-particle excitations in certain regime of the parameters. The retarded Green's functions are plotted at specific values of parameters in $D=4$, where the specific heat is linear in the temperature and the quasi-particle excitation exists. We also calculate the AC conductivity in $D$-dimensions as a by-product.Comment: 29 pages, 1 figur

Adult mortality of diseases and injuries attributable to selected metabolic, lifestyle, environmental, and infectious risk factors in Taiwan: A comparative risk assessment

Background: To facilitate priority-setting in health policymaking, we compiled the best available information to estimate the adult mortality (>30 years) burden attributable to 13 metabolic, lifestyle, infectious, and environmental risk factors in Taiwan. Methods: We obtained data on risk factor exposure from nationally representative health surveys, cause-specific mortality from the National Death Registry, and relative risks from epidemiological studies and meta-analyses. We applied the comparative risk assessment framework to estimate mortality burden attributable to individual risk factors or risk factor clusters. Results: In 2009, high blood glucose accounted for 14,900 deaths (95% UI: 11,850-17,960), or 10.4% of all deaths in that year. It was followed by tobacco smoking (13,340 deaths, 95% UI: 10,330-16,450), high blood pressure (11,190 deaths, 95% UI: 8,190-14,190), ambient particulate matter pollution (8,600 deaths, 95% UI: 7,370-9,840), and dietary risks (high sodium intake and low intake of fruits and vegetables, 7,890 deaths, 95% UI: 5,970-9,810). Overweight-obesity and physical inactivity accounted for 7,620 deaths (95% UI: 6,040-9,190), and 7,400 deaths (95% UI: 6,670-8,130), respectively. The cardiometabolic risk factors of high blood pressure, high blood glucose, high cholesterol, and overweight-obesity jointly accounted for 12,120 deaths (95% UI: 11,220-13,020) from cardiovascular diseases. For domestic risk factors, infections from hepatitis B virus (HBV) and hepatitis C virus (HCV) were responsible for 6,300 deaths (95% UI: 5,610-6,980) and 3,170 deaths (95% UI: 1,860-4,490), respectively, and betel nut use was associated with 1,780 deaths from oral, laryngeal, and esophageal cancer (95% UI: 1,190-2,360). The leading risk factors for years of life lost were similar, but the impact of tobacco smoking and alcohol use became larger because the attributable deaths from these risk factors occurred among young adults aged less than 60 years. Conclusions: High blood glucose, tobacco smoking, and high blood pressure are the major risk factors for deaths from diseases and injuries among Taiwanese adults. A large number of years of life would be gained if the 13 modifiable risk factors could be removed or reduced to the optimal level

Interplay between SIRT1 and hepatitis B virus X protein in the activation of viral transcription

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Assessment of SARS-CoV-2 Immunity in Convalescent Children and Adolescents

Persistence of protective immunity for SARS-CoV-2 is important against reinfection. Knowledge on SARS-CoV-2 immunity in pediatric patients is currently lacking. We opted to assess the SARS-CoV-2 adaptive immunity in recovered children and adolescents, addressing the pediatrics specific immunity towards COVID-19. Two independent assays were performed to investigate humoral and cellular immunological memory in pediatric convalescent COVID-19 patients. Specifically, RBD IgG, CD4+, and CD8+ T cell responses were identified and quantified in recovered children and adolescents. SARS-CoV-2-specific RBD IgG detected in recovered patients had a half-life of 121.6 days and estimated duration of 7.9 months compared with baseline levels in controls. The specific T cell response was shown to be independent of days after diagnosis. Both CD4+ and CD8+ T cells showed robust responses not only to spike (S) peptides (a main target of vaccine platforms) but were also similarly activated when stimulated by membrane (M) and nuclear (N) peptides. Importantly, we found the differences in the adaptive responses were correlated with the age of the recovered patients. The CD4+ T cell response to SARS-CoV-2 S peptide in children aged <12 years correlated with higher SARS-CoV-2 RBD IgG levels, suggesting the importance of a T cell-dependent humoral response in younger children under 12 years. Both cellular and humoral immunity against SARS-CoV-2 infections can be induced in pediatric patients. Our important findings provide fundamental knowledge on the immune memory responses to SARS-CoV-2 in recovered pediatric patients