Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP-eIF4G-eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27-PABP-eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP-eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non-poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP-eIF4G complex in translation initiation

Microcredit, the corporatization of nongovernmental organizations, and academic activism: The example of Professor Anu Muhammad

Based on an interview with academic-activist Professor Anu Muhammad, this edited transcript illuminates the corporatization of nongovernmental organizations, with specific reference to perpetuating the negative effects of neoliberal microcredit practices in developing countries. It focuses upon how such corporatization is contributing to corruption and the weakened role of the state. The concept of poor-people-led cooperatives is proposed as an alternative as they are more congruent with actively maintaining cultural traditions, protecting social cohesion, and mobilizing collective community-level energy to alleviate misery and reduce poverty

Landslide initiation and runout susceptibility modeling in the context of hill cutting and rapid urbanization: a combined approach of weights of evidence and spatial multi-criteria

Rainfall induced landslides are a common threat to the communities living on dangerous hill-slopes in Chittagong Metropolitan Area, Bangladesh. Extreme population pressure, indiscriminate hill cutting, increased precipitation events due to global warming and associated unplanned urbanization in the hills are exaggerating landslide events. The aim of this article is to prepare a scientifically accurate landslide susceptibility map by combining landslide initiation and runout maps. Land cover, slope, soil permeability, surface geology, precipitation, aspect, and distance to hill cut, road cut, drainage and stream network factor maps were selected by conditional independence test. The locations of 56 landslides were collected by field surveying. A weight of evidence (WoE) method was applied to calculate the positive (presence of landslides) and negative (absence of landslides) factor weights. A combination of analytical hierarchical process (AHP) and fuzzy membership standardization (weighs from 0 to 1) was applied for performing a spatial multi-criteria evaluation. Expert opinion guided the decision rule for AHP. The Flow-R tool that allows modeling landslide runout from the initiation sources was applied. The flow direction was calculated using the modified Holmgren’s algorithm. The AHP landslide initiation and runout susceptibility maps were used to prepare a combined landslide susceptibility map. The relative operating characteristic curve was used for model validation purpose. The accuracy of WoE, AHP, and combined susceptibility map was calculated 96%, 97%, and 98%, respectively

Direct Stimulation of Translation by the Multifunctional Herpesvirus ICP27 Protein

Herpes simplex virus type 1 (HSV-1) ICP27 protein is an essential regulator of viral gene expression with roles at various levels of RNA metabolism in the nucleus. Using the tethered function assay, we showed a cytoplasmic activity for ICP27 in directly enhancing mRNA translation in vivo in the absence of other viral factors. The region of ICP27 required for translational stimulation maps to the C terminus. Furthermore, in infected cells, ICP27 is associated with polyribosomes, indicating a function in translation during the lytic cycle

Effect of intracoronary bone marrow-derived mononuclear cell injection early and late after myocardial infarction on CMR-derived myocardial strain

BACKGROUND: Studies indicate no clear impact of intracoronary injection of bone-marrow unselected mononuclear cells (BM-MNC) after acute myocardial infarction (AMI) on left-ventricular function (LVEF). Strain parameters by cardiovascular magnetic resonance (CMR) have been proposed to be more sensitive to functional changes of the heart. The aim of the present study was to assess changes of global longitudinal (GLS) and circumferential strain (GCS) in a group of patients treated with BM-MNC after AMI. METHODS: One-hundred and forty-nine patients with successfully reperfused AMI and LV dysfunction (LVEF<45%) were retrospectively included into this sub-study of the SWISS-AMI multicentre trial. Patients were divided into control (N = 54), early (5-7 days after AMI, N = 51) and late BM-MNC treatment groups (3-4 weeks, N = 44). The endpoint was the change of GLS and GCS as obtained from cine sequences 4 and 12 months after AMI using feature tracking algorithm. RESULTS: In unadjusted analyses, the absolute change of GLS for the early treatment group from baseline to 4 months was 2.5 ± 4.3 (p < 0.01), to 12 months 2.7 ± 5.7% (p = 0.004). For late treatment, it was 1.5 ± 4.0% (p = 0.039, 4 months) and 2.5 ± 5.6% (p = 0.015, 12 months). For controls 0.7 ± 4.7% (p = 0.378), 0.8 ± 3.9% (p = 0.253) respectively. Adjusting for different baseline values, neither an overall treatment effect (both time-points) of BM-MNC nor a treatment time-related (only early or late) effect could be shown for all functional parameters. CONCLUSIONS: Among patients after AMI with successful reperfusion and LV dysfunction, intracoronary infusion of BM-MNC early or late after AMI did not improve global strain parameters at 4- or 12-months follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186