bims-hypusi 2024-07-21 papers

Issue of 2024‒07‒21
two papers selected by
Sebastian J. Hofer, University of Graz

Heliyon. 2024 Jul 15. 10(13): e33838

Analysis of the effect of hypusination in myeloid cells on colitis and colitis-associated cancer.

Alain P Gobert, Jordan Finley, Mohammad Asim, Daniel P Barry, Margaret M Allaman, Caroline V Hawkins, Kamery J Williams, Alberto G Delagado, Raghavendra G Mirmira, Shilin Zhao, M Blanca Piazuelo, M Kay Washington, Lori A Coburn, Keith T Wilson.

Hypusine is an amino acid synthesized by the enzyme deoxyhypusine synthase (DHPS). It is critical for the activity of eukaryotic translation initiation factor 5A (EIF5A). We reported that hypusination i) in macrophages supports the innate response towards pathogenic bacteria and ii) in epithelial cells maintains intestinal homeostasis. Herein, we investigated the effect of myeloid hypusination on the outcome of colitis and colitis-associated cancer. We found that patients with Crohn's disease exhibit increased levels of DHPS and EIF5AHyp in cells infiltrating the colon lamina propria. However, the specific deletion of Dhps in myeloid cells had no impact on clinical, histological, or inflammatory parameters in mice treated with dextran sulfate sodium (DSS). Further, tumorigenesis and level of dysplasia were not affected by myeloid deletion of Dhps in the azoxymethane-DSS model. The composition of the fecal and the mucosa-associated microbiome was similar in animals lacking or not DHPS in myeloid cells. Thus, hypusination in myeloid cells does not regulate colitis associated with epithelial injury and colitis-associated cancer. Enhancement of the DHPS/hypusine pathway in patients with inflammatory bowel disease could have therapeutic impact through epithelial effects, but modulation of hypusination in myeloid cells will be unlikely to affect the disease.

Keywords: Colon; Colorectal cancer; Gut microbiota; Hypusine; Inflammation; Inflammatory bowel diseases

DOI: https://doi.org/10.1016/j.heliyon.2024.e33838

bioRxiv. 2024 Jul 13. pii: 2024.07.10.602410. [Epub ahead of print]

eIF1 and eIF5 dynamically control translation start site fidelity.

Rosslyn Grosely, Carlos Alvarado, Ivaylo P Ivanov, Oliver B Nicholson, Joseph D Puglisi, Thomas E Dever, Christopher P Lapointe.

Translation initiation defines the identity of a synthesized protein through selection of a translation start site on a messenger RNA. This process is essential to well-controlled protein synthesis, modulated by stress responses, and dysregulated in many human diseases. The eukaryotic initiation factors eIF1 and eIF5 interact with the initiator methionyl-tRNA i Met on the 40S ribosomal subunit to coordinate start site selection. Here, using single-molecule analysis of in vitro reconstituted human initiation combined with translation assays in cells, we examine eIF1 and eIF5 function. During translation initiation on a panel of RNAs, we monitored both proteins directly and in real time using single-molecule fluorescence. As expected, eIF1 loaded onto mRNAs as a component of the 43S initiation complex. Rapid (∼ 2 s) eIF1 departure required a translation start site and was delayed by alternative start sites and a longer 5' untranslated region (5'UTR). After its initial departure, eIF1 rapidly and transiently sampled initiation complexes, with more prolonged sampling events on alternative start sites. By contrast, eIF5 only transiently bound initiation complexes late in initiation immediately prior to association of eIF5B, which allowed joining of the 60S ribosomal subunit. eIF5 association required the presence of a translation start site and was inhibited and destabilized by alternative start sites. Using both knockdown and overexpression experiments in human cells, we validated that eIF1 and eIF5 have opposing roles during initiation. Collectively, our findings demonstrate how multiple eIF1 and eIF5 binding events control start-site selection fidelity throughout initiation, which is tuned in response to changes in the levels of both proteins.

DOI: https://doi.org/10.1101/2024.07.10.602410