Hrs Promotes Ubiquitination and Mediates Endosomal Trafficking of Smoothened in Drosophila Hedgehog Signaling

In Hedgehog (Hh) signaling, the seven-transmembrane protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation, ubiquitination, and cell surface accumulation. However, it is not clear how Smo cell surface accumulation and intracellular trafficking are regulated. Here, we demonstrate that inactivation of Hrs by deletion or RNAi accumulates Smo in the late endosome that is marked by late endosome markers. Inactivation of Hrs enhances the wing defects caused by dominant-negative Smo. We show that Hrs promotes Smo ubiquitination, deleting the ubiquitin-interacting-motif (UIM) in Hrs abolishes the ability of Hrs to regulate Smo ubiquitination. However, the UIM domain neither recognizes the ubiquitinated Smo nor directly interacts with Smo. Hrs lacking UIM domain still downregulates Smo activity even though to a less extent. We have characterized that the N-terminus of Hrs directly interacts with the PKA/CK1 phosphorylation clusters to prevent Smo phosphorylation and activation, indicating an ubiquitin-independent regulation of Smo by Hrs. Finally, we found that knockdown of Tsg101 accumulates Smo that is co-localized with Hrs and other late endosome markers. Taken together, our data indicate that Hrs mediates Smo trafficking in the late endosome by not only promoting Smo ubiquitination but also blocking Smo phosphorylation

Reservoir automatic history matching: Methods, challenges, and future directions

Reservoir history matching refers to the process of continuously adjusting the parameters of the reservoir model, so that its dynamic response will match the historical observation data, which is a prerequisite for making forecasts based on the reservoir model. With the development of optimization theory and machine learning algorithms, automatic history matching has made numerous breakthroughs for practical applications. In this perspective, the existing automatic history matching methods are summarized and divided into model-driven and surrogate-driven history matching methods according to whether the reservoir simulator needs to be run during the automatic history matching process. Then, the basic principles of these methods and their limitations in practical applications are outlined. Finally, the future trends of reservoir automatic history matching are discussed.Cited as: Liu, P., Zhang, K., Yao, J. Reservoir automatic history matching: Methods, challenges, and future directions. Advances in Geo-Energy Research, 2023, 7(2): 136-140. https://doi.org/10.46690/ager.2023.02.0