RESUMO
BACKGROUND: Homeostasis of autophagy under normal conditions and nutrient stress is maintained by adaptive activation of regulatory proteins. However, the protein-lipid crosstalk that modulates the switch from suppression to activation of autophagy initiation is largely unknown. RESULTS: Here, we show that human diazepam-binding inhibitor (DBI), also known as acyl-CoA binding protein (ACBP), binds to phosphatidylethanolamine of the phagophore membrane under nutrient-rich growth conditions, leading to inhibition of LC3 lipidation and suppression of autophagy initiation. Specific residues, including the conserved tyrosine residues of DBI, interact with phosphatidylethanolamine to stabilize the later molecule in the acyl-CoA binding cavity of the protein. Under starvation, phosphorylation of serine-21 of DBI mediated by the AMP-activated protein kinase results in a drastic reduction in the affinity of the protein for phosphatidylethanolamine. The release of serine-21 phosphorylated DBI from the phagophore upon nutrient starvation restores the high LC3 lipidation flux and maturation of the phagophore to autophagosome. CONCLUSION: DBI acts as a strategic barrier against overactivation of phagophore maturation under nutrient-rich conditions, while triggering autophagy under nutrient-deficient conditions.
Assuntos
Proteínas de Transporte , Fosfatidiletanolaminas , Humanos , Autofagia , Nutrientes , SerinaRESUMO
Primary cilia are non-motile sensory cell-organelle that are essential for organismal development, differentiation, and postnatal homeostasis. Their biogenesis and function are mediated by the intraflagellar transport (IFT) system. Pathogenic variants in IFT52, a central component of the IFT-B complex is associated with short-rib thoracic dysplasia with or without polydactyly 16 (SRTD16), with major skeletal manifestations, in addition to other features. Here we sought to examine the role of IFT52 in osteoblast differentiation. Using lentiviral shRNA interference Ift52 was depleted in C3H10T1/2 mouse mesenchymal stem cells. This led to the disruption of the IFT-B anterograde trafficking machinery that impaired primary ciliogenesis and blocked osteogenic differentiation. In Ift52 silenced cells, Hedgehog (Hh) pathway upregulation during osteogenesis was attenuated and despite Smoothened Agonist (SAG) based Hh activation, osteogenic differentiation was incompletely restored. Further we investigated IFT52 activity in Drosophila, wherein the only ciliated somatic cells are the bipolar sensory neurons of the peripheral nervous system. Knockdown of IFT52 in Drosophila neuronal tissues reduced lifespan with the loss of embryonic chordotonal cilia, and produced severe locomotion, auditory and proprioceptive defects in larva and adults. Together these findings improve our knowledge of the role of IFT52 in various physiological contexts and its associated human disorder.
Assuntos
Proteínas Hedgehog , Osteogênese , Animais , Proteínas de Transporte/metabolismo , Cílios/metabolismo , Drosophila/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Osteogênese/genética , Percepção , Transporte Proteico/genética , Costelas/metabolismoRESUMO
Coronavirus disease caused by the SARS-CoV-2 virus has emerged as a global challenge in terms of health and disease monitoring. COVID-19 infection is mainly spread through the SARS-CoV-2 infection leading to the development of mild to severe clinical manifestations. The virus binds to its cognate receptor ACE2 which is widely expressed among different tissues in the body. Notably, SARS-CoV-2 shedding in the fecal samples has been reported through the screening of sewage water across various countries. Wastewater screening for the presence of SARS-CoV-2 provides an alternative method to monitor infection threat, variant identification, and clinical evaluation to restrict the virus progression. Multiple cohort studies have reported the application of wastewater treatment approaches and epidemiological significance in terms of virus monitoring. Thus, the manuscript outlines consolidated and systematic information regarding the application of wastewater-based epidemiology in terms of monitoring and managing a viral disease outbreak like COVID-19.
RESUMO
The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a wide spectrum of clinical phenotypes ranging from asymptomatic to symptomatic with mild or moderate presentation and severe disease. COVID-19 susceptibility, severity and recovery have demonstrated high variability worldwide. Variances in the host genetic architecture may underlie the inter-individual and population-scale differences in COVID-19 presentation. We performed a genome-wide association analysis employing the genotyping data from AncestryDNA for COVID-19 patients of European descent and used asymptomatic subjects as the control group. We identified 621 genetic variants that were significantly distinct between asymptomatic and acutely symptomatic COVID-19 patients (multiple-testing corrected p-value < 0.001). These variants were found to be associated with pathways governing host immunity, such as interferon, interleukin and cytokine signalling, and known COVID-19 comorbidities, such as obesity and cholesterol metabolism. Further, our ancestry analysis revealed that the asymptomatic COVID-19 patients possess discernibly higher proportions of the Ancestral North Eurasian (ANE) and Eastern Hunter-Gatherer (EHG) ancestry, which was introduced to Europe through Bell Beaker culture (Yamnaya related) and lower fractions of Western Hunter-Gatherer (WHG) ancestry, while severely symptomatic patients have higher fractions of WHG and lower ANE/EHG ancestral components, thereby delineating the likely ancestral differences between the two groups.
RESUMO
Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) outbreak is a major public health concern, which has accounted for >1.7 million deaths across the world. A surge in the case fatality ratio as compared with the infection ratio has been observed in most of the countries. The novel Coronavirus SARS-CoV-2 shares the most common sequence with SARS-CoV, but it has a higher rate of transmission. The SARS-CoV-2 pathogenesis is initiated by the binding of viral spike protein with the target receptor Angiotensin-Converting Enzyme 2 (ACE2) facilitating virus internalization within host cells. SARS-CoV-2 mainly causes alveolar damage ranging from mild to severe clinical respiratory manifestations. Most of the cases have revealed the association of Coronavirus disease with patients having earlier comorbidities like Hypertension, Diabetes mellitus, and Cerebrovascular diseases. Pharmacological investigation of the SARS-Cov-2 patients has revealed the frequent use of drugs belongs to Angiotensin-converting enzyme inhibitors (ACEi) and/or Angiotensin II type I receptor blockers (ARBs). Interestingly, a significant increase in ACE2 expression was noticed in patients routinely treated with the above group of drugs were also reported. To date, the association of ACEi and/or ARBs with the up-regulation of ACE2 expression has not been defined distinctively. The proposed review will focus on the pathways which are responsible for the upregulation of ACE2 and its impact on gravity of SARS-CoV-2 disease.