scholarly journals Acetyl-CoA flux from the cytosol to the ER regulates engagement and quality of the secretory pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Inca A. Dieterich ◽  
Yusi Cui ◽  
Megan M. Braun ◽  
Alexis J. Lawton ◽  
Nicklaus H. Robinson ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Secretory Pathway ◽  
Severe Disease ◽  
Lysine Acetylation ◽  
Acetyl Coa ◽  
Disease Phenotypes ◽  
Membrane Protein Trafficking ◽  
Duplication Events ◽  
Glycan Modification

AbstractNε-lysine acetylation in the ER is an essential component of the quality control machinery. ER acetylation is ensured by a membrane transporter, AT-1/SLC33A1, which translocates cytosolic acetyl-CoA into the ER lumen, and two acetyltransferases, ATase1 and ATase2, which acetylate nascent polypeptides within the ER lumen. Dysfunctional AT-1, as caused by gene mutation or duplication events, results in severe disease phenotypes. Here, we used two models of AT-1 dysregulation to investigate dynamics of the secretory pathway: AT-1 sTg, a model of systemic AT-1 overexpression, and AT-1S113R/+, a model of AT-1 haploinsufficiency. The animals displayed reorganization of the ER, ERGIC, and Golgi apparatus. In particular, AT-1 sTg animals displayed a marked delay in Golgi-to-plasma membrane protein trafficking, significant alterations in Golgi-based N-glycan modification, and a marked expansion of the lysosomal network. Collectively our results indicate that AT-1 is essential to maintain proper organization and engagement of the secretory pathway.

scholarly journals Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation

2016 ◽  
Vol 213 (7) ◽  
pp. 1267-1284 ◽  
Author(s):  
Rikki Hullinger ◽  
Mi Li ◽  
Jingxin Wang ◽  
Yajing Peng ◽  
James A. Dowell ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Secretory Pathway ◽  
Premature Death ◽  
Autism Spectrum ◽  
Lysine Acetylation ◽  
Acetyl Coa ◽  
Dendritic Branching ◽  
Familial Spastic Paraplegia ◽  
Epigenetic Modulation ◽  
Mitochondrial Adaptation

The import of acetyl-CoA into the lumen of the endoplasmic reticulum (ER) by AT-1/SLC33A1 regulates Nε-lysine acetylation of ER-resident and -transiting proteins. Specifically, lysine acetylation within the ER appears to influence the efficiency of the secretory pathway by affecting ER-mediated quality control. Mutations or duplications in AT-1/SLC33A1 have been linked to diseases such as familial spastic paraplegia, developmental delay with premature death, and autism spectrum disorder with intellectual disability. In this study, we generated an AT-1 Tg mouse model that selectively overexpresses human AT-1 in neurons. These animals demonstrate cognitive deficits, autistic-like social behavior, aberrations in synaptic plasticity, an increased number of dendritic spines and branches, and widespread proteomic changes. We also found that AT-1 activity regulates acetyl-CoA flux, causing epigenetic modulation of the histone epitope H3K27 and mitochondrial adaptation. In conclusion, our results indicate that increased expression of AT-1 can cause an autistic-like phenotype by affecting key neuronal metabolic pathways.

scholarly journals Endoplasmic reticulum acetyltransferases Atase1 and Atase2 differentially regulate reticulophagy, macroautophagy and cellular acetyl-CoA metabolism

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael J. Rigby ◽  
Alexis J. Lawton ◽  
Gulpreet Kaur ◽  
Varuna C. Banduseela ◽  
William E. Kamm ◽  
...  
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Control Mechanism ◽  
Cellular Biology ◽  
Lysine Acetylation ◽  
Type Ii ◽  
Acetyl Coa ◽  
Toxic Protein ◽  
Quality Control Mechanism

AbstractNε-lysine acetylation in the ER lumen is a recently discovered quality control mechanism that ensures proteostasis within the secretory pathway. The acetyltransferase reaction is carried out by two type-II membrane proteins, ATase1/NAT8B and ATase2/NAT8. Prior studies have shown that reducing ER acetylation can induce reticulophagy, increase ER turnover, and alleviate proteotoxic states. Here, we report the generation of Atase1−/− and Atase2−/− mice and show that these two ER-based acetyltransferases play different roles in the regulation of reticulophagy and macroautophagy. Importantly, knockout of Atase1 alone results in activation of reticulophagy and rescue of the proteotoxic state associated with Alzheimer’s disease. Furthermore, loss of Atase1 or Atase2 results in widespread adaptive changes in the cell acetylome and acetyl-CoA metabolism. Overall, our study supports a divergent role of Atase1 and Atase2 in cellular biology, emphasizing ATase1 as a valid translational target for diseases characterized by toxic protein aggregation in the secretory pathway.

Does Infliximab Short Infusion have a Beneficial Impact on the Quality of Life in Patients with Inflammatory Bowel Diseases? A Single Centre Prospective Evaluation

2015 ◽  
Vol 24 (2) ◽  
pp. 165-170 ◽  
Author(s):  
Mariabeatrice Principi ◽  
Giuseppe Losurdo ◽  
Rosa Federica La Fortezza ◽  
Pasquale Lopolito ◽  
Rosa Lovero ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Inflammatory Bowel Diseases ◽  
Adverse Reactions ◽  
Severe Disease ◽  
Sexual Life ◽  
Necrosis Factor Alpha ◽  
Short Infusion ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Background & Aims: Infliximab (IFX) is an anti-tumor necrosis factor alpha agent used in inflammatory bowel diseases (IBD) therapy. Usually, it is administered over a 2-hour intravenous infusion. However, shortening the infusion duration to 1 hour has proved to be feasible and safe. In the present study we evaluated whether shortening the IFX infusion could affect the patients' quality of life (QoL) compared to the standard protocol.Methods: Subjects affected by IBD receiving IFX were prospectively recruited. The main criterion to shorten the infusion was the absence of IFX-related adverse reactions during the previous three 2-h infusions. For each patient, demographic, clinical and anthropometric data were collected. A questionnaire investigating their overall/job/social/sexual QoL was administered. Ordinal regression was performed with odds ratios (OR) for significant independent variables.Results: Eighty-one patients were included (46 with ulcerative colitis - UC, 35 with Crohn's disease - CD). Sixteen received the 2-h infusion due to previous adverse reactions, and the remaining 65 underwent the 1-h schedule. Shortening the infusion to 1 hour determined a better QoL (OR=0.626). However, the QoL was negatively influenced by age (OR=1.023), female sex (OR=2.04) and severe disease activity (OR=7.242). One-hour IFX infusion induced a better outcome on work (OR=0.588) and social (OR=0.643) QoL. Long-standing disease was correlated with a slightly better sexual QoL (OR=0.93). Conversely, older age (OR=1.046), severe clinical score (OR=15.579), use of other immunomodulators (OR=3.693) and perianal CD (OR=3.265) were related to an unsatisfactory sexual life. The total number of infusions (OR=0.891), proctitis (OR=0.062) or pancolitis (OR=0.1) minimized the perception of infusion-related side effects.Conclusion: The 1-h short infusion improves overall, social and job QoL, so that, when indicated, it should be recommended.

Sirtuin-dependent reversible lysine acetylation controls the activity of acetyl-Coenzyme A synthetase in Campylobacter jejuni

2021 ◽  
Author(s):  
Victoria L. Jeter ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Campylobacter Jejuni ◽  
Posttranslational Modifications ◽  
Active Site ◽  
Protein Function ◽  
Metabolic Enzyme ◽  
Lysine Acetylation ◽  
Class Iii ◽  
Acetyl Coa

Posttranslational modifications are mechanisms for rapid control of protein function used by cells from all domains of life. Acetylation of the epsilon amino group ( N ε ) of an active-site lysine of the AMP-forming acetyl-CoA synthetase (Acs) enzyme is the paradigm for the posttranslational control of the activity of metabolic enzymes. In bacteria, the alluded active-site lysine of Acs enzymes can be modified by a number of different GCN5-type N -acetyltransferases (GNATs). Acs activity is lost as a result of acetylation, and restored by deacetylation. Using a heterologous host, we show that Campylobacter jejuni NCTC11168 synthesizes enzymes that control Acs function by reversible lysine acetylation (RLA). This work validates the function of gene products encoded by the cj1537c , cj1715, and cj1050c loci, namely the AMP-forming acetate:CoA ligase ( Cj Acs), a type IV GCN5-type lysine acetyltransferase (GNAT, hereafter Cj LatA), and a NAD + -dependent (class III) sirtuin deacylase ( Cj CobB), respectively. To our knowledge, these are the first in vivo and in vitro data on C. jejuni enzymes that control the activity of Cj Acs. IMPORTANCE This work is important because it provides the experimental evidence needed to support the assignment of function to three key enzymes, two of which control the reversible posttranslational modification of an active-site lysyl residue of the central metabolic enzyme acetyl-CoA synthetase ( Cj Acs). We can now generate Campylobacter jejuni mutant strains defective in these functions, so we can establish the conditions in which this mode of regulation of Cj Acs is triggered in this bacterium. Such knowledge may provide new therapeutic strategies for the control of this pathogen.

Data Quality of Longitudinally Collected Patient-Reported Outcomes (PROs) after Thoracic Surgery: A Comparison of Paper- and Web-Based Assessments (Preprint)

2021 ◽  
Author(s):  
Hongfan Yu ◽  
Qingsong Yu ◽  
Yuxian Nie ◽  
Wei Xu ◽  
Yang Pu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Thoracic Surgery ◽  
Data Quality ◽  
Severe Disease ◽  
Sampling Bias ◽  
Patient Reported Outcome ◽  
Web Based ◽  
Quality Of Life Scale ◽  
Patient Reported

BACKGROUND High-frequent patient-reported outcome (PRO) assessments are used to measure patients’ symptoms after surgery for surgical research; however, quality of those longitudinal PRO data has seldom been discussed. OBJECTIVE To describe errors, to identify factors influencing the data quality, and to profile error trajectories of data longitudinally collected via paper-and-pencil (P&P) or web-based-assessment (ePRO) after thoracic surgery. METHODS We extracted longitudinal PRO data from two prospective clinical studies. PROs were assessed by the MD Anderson Symptom Inventory Lung Cancer Module and single-item Quality of Life Scale before surgery and then daily after surgery until discharge or up to 14 days of hospitalization. Patient compliance and data error were identified and compared between P&P and ePRO. Generalized estimating equations models and two-piecewise models were used to describe trajectories of error incidence over time and to identify the risk factors. RESULTS Among 629 patients with at least 2 PRO assessments, 440 completed 3347 P&P assessments and 189 completed 1291 ePRO assessments. In total, 49.44% of patients had at least 1 error, including 1) missing items (64.69%), 2) modifications without signatures (27.99%), 3) selection of multiple options (3.02%), 4) missing patient signatures (2.54%), 5) missing researcher signatures (1.45%) and 6) missing completion dates (0.3%). ePRO patients had fewer errors than P&P patients (30.16% vs. 57.73%, p <0.0001). Compared with ePRO patients, those using P&P were older, less educated and sicker. Common risk factors of having errors were with a lower education level (P&P, OR=1.39, 95%CL=1.20-1.62, p<.0001; ePRO, OR=1.82, 95%CI=1.22-2.72, p=0.0032), treated in a provincial hospital (P&P, OR=3.34, 95%CI=2.10-5.33, p<.0001; ePRO, OR=4.73, 95%CI=2.18-10.25, p<.0001) and with severe disease (P&P, OR=1.63, 95%CI=1.33-1.99, p<.0001; ePRO, OR=2.70, 95%CI=1.53-4.75, p=0.0006). Errors peaked on postoperative day (POD) 1 for P&P, and on POD 2 for ePRO. CONCLUSIONS ePRO might be superior to P&P in terms of data quality. However, sampling bias needs to be considered for studies using longitudinal PROs as major outcomes.

scholarly journals PROFILE OF PATIENTS RECEIVING TOTAL KNEE ARTHROPLASTY: A CROSS-SECTIONAL STUDY

2017 ◽  
Vol 25 (5) ◽  
pp. 202-205 ◽  
Author(s):  
MARCELO JOSÉ CORTEZ BEZERRA ◽  
IGOR MAGALHÃES BARBOSA ◽  
THALES GONÇALVES DE SOUSA ◽  
LARISSA MEIRELES FERNANDES ◽  
DIEGO LEONARDO MENEZES MAIA ◽  
...  
Keyword(s):  
Medical Records ◽  
Severe Disease ◽  
Functional Limitation ◽  
Cross Sectional Study ◽  
Level Of Evidence ◽  
Cross Sectional ◽  
Lequesne Index ◽  
Total Knee ◽  
Epidemiological Profile

ABSTRACT Objective: To describe the epidemiological profile, presented deformities, associated comorbidities, and impact on quality of life in patients with knee osteoarthritis. This study was conducted in a philanthropic hospital in Fortaleza from 2014 to 2015. Methods: Data were collected from medical records, epidemiological forms, and by applying the Lequesne index questionnaire, which contains several questions related to pain, discomfort and functional limitation to assess the severity of symptoms. Results: Females were more prevalent (76.7%), as were patients over 65 years of age (61.6%) and non-whites (81.6%). As for comorbidities, 83.3% had hypertension and 31.7% had diabetes. Of the total, 76.5% cases were genu varum, and 23.5% genu valgum. According to the Lequesne index findings, 61.6% cases were “extremely severe,” and women had higher scores. Conclusion: Females were more prevalent and whites were less prevalent. The most frequent comorbidity was hypertension. Female and elderly patients have more severe disease according to Lequesne index score, and these findings were statistically significant. Level of Evidence II, Prospective Study.

scholarly journals The Patient Level Cost of Asthma in Adults in South Central Ontario

1998 ◽  
Vol 5 (6) ◽  
pp. 463-471 ◽  
Author(s):  
Wendy J Ungar ◽  
Peter C Coyte ◽  
Kenneth R Chapman ◽  
Linda MacKeigan ◽  
Keyword(s):  
Cost Of Illness ◽  
Hospital Admissions ◽  
Severe Disease ◽  
Indirect Costs ◽  
Provincial Government ◽  
Multiple Perspectives ◽  
Drug Plan ◽  
Medication Costs ◽  
South Central

OBJECTIVE: To assess the annual cost of asthma per adult patient from the perspectives of society, the Ontario Ministry of Health and the patient.DESIGN: Prospective cost of illness evaluation.SETTING: Ambulatory out-patients residing in southern central Ontario.POPULATION STUDIED: Nine hundred and forty patients with asthma over 15 years of age studied between May 1995 and April 1996.OUTCOME MEASURES: Direct costs, such as respiratory-related visits to general/family practitioners, respiratory specialists, emergency rooms, hospital admissions, laboratory tests, prescription medications, dispensing fees, devices and out-of-pocket expenses, were calculated. Indirect costs, such as absences from work or usual activities, and travel and waiting time, were studied.MAIN RESULTS: Unadjusted annual costs were $2,550 per patient. Hospitalizations and medications each accounted for 22% of the total cost and indirect costs 50% of the total costs. More severe disease, older age, smoking, drug plan availability and retirement were significant predictors of costs. Annual costs per patient varied from $1,255 (95% CI $1,061 to $1,485) in young nonsmokers with no drug plan and mild disease to $5,032 (95% CI $4,347 to $5,825) in older smokers with drug plans and severe disease. Clinically important reductions in the quality of life occurred with increasing severity.CONCLUSIONS: Interventions aimed at reducing productivity losses, admissions to hospital and medication costs may result in savings to society, the provincial government and the patient. The quality of policy and allocation decisions may be enhanced by cost of illness estimates that are comprehensive, precise and incorporate multiple perspectives.

scholarly journals A rapid and affordable screening platform for membrane protein trafficking

BMC Biology ◽  
2015 ◽  
Vol 13 (1) ◽  
Author(s):  
Joshua C. Snyder ◽  
Thomas F. Pack ◽  
Lauren K. Rochelle ◽  
Subhasish K. Chakraborty ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Trafficking ◽  
Membrane Protein Trafficking ◽  
Screening Platform

scholarly journals Nail Involvement in Patients with Psoriatic Arthritis in Northern Iran

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
O. Zargari ◽  
E. Kazemnezhad Leyli ◽  
S. Z. Azimi
Keyword(s):  
Psoriatic Arthritis ◽  
Severe Disease ◽  
Cross Sectional Study ◽  
Joint Involvement ◽  
Sectional Study ◽  
Northern Iran ◽  
Cross Sectional ◽  
The Relationship ◽  
Nail Involvement

Background. Psoriatic arthritis (PsA) results in an increased burden of psoriasis and impairs both quality of life and an individual’s functional capacity. The relationship between nail involvement and PsA in psoriasis is not fully characterized. Aim. To evaluate the frequency and characteristics of nail involvement in psoriatic patients and to assess the relationship with joint involvement. Methods. A total of 197 patients with moderate-to-severe psoriasis were consecutively invited to participate in this cross-sectional study. The patients are divided into two groups: those with and those without psoriatic arthritis. Results. 69.5% of psoriatic (137 out of 197) patients had nail involvement. The most common nail abnormality was onycholysis, followed by pitting and oil droplet changes. Nail involvement was more common in patients with psoriatic arthritis (82.1% versus 57.8%, p=0.001). Conclusion. Nail involvement is commonly associated with PsA. Onycholysis, splinter hemorrhage, and oil drop were significantly more common in the PsA group as opposed to patients with just skin findings. In general, psoriatic patients with arthritis had more severe disease.

Ethanol and Membrane Protein Trafficking: Diverse Mechanisms of Ethanol Action

2002 ◽  
Vol 26 (2) ◽  
pp. 287-293 ◽  
Author(s):  
Laura E. Nagy ◽  
M. Raj Lakshman ◽  
Carol A. Casey ◽  
Cynthia F. Bearer
Keyword(s):  
Membrane Protein ◽  
Protein Trafficking ◽  
Membrane Protein Trafficking
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