bims-ershed 2023-02-19 papers

bioRxiv. 2023 Feb 09. pii: 2023.02.09.527889. [Epub ahead of print]

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes.

Anit Shah, Ian Huck, Kaylia Duncan, Erica R Gansemer, Udayan Apte, Mark A Stamnes, D Thomas Rutkowski.

In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Several pathways potentially link HNF4α to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4α activity is linked to hepatic ER homeostasis through multiple mechanisms.

DOI: https://doi.org/10.1101/2023.02.09.527889

Biophys J. 2023 Feb 10. pii: S0006-3495(22)03632-3. [Epub ahead of print]122(3S1): 510a

The impact of endoplasmic reticulum morphology on IRE1 protein clustering.

Liam Kischuck, Aidan Brown.

DOI: https://doi.org/10.1016/j.bpj.2022.11.2716

Biophys J. 2023 Feb 10. pii: S0006-3495(22)01464-3. [Epub ahead of print]122(3S1): 63a

Controlling htt protein aggregation to assess toxicity in Caenorhabditis elegans.

Ephraim C Ezeigbo, Justin A Legleiter.

DOI: https://doi.org/10.1016/j.bpj.2022.11.548

Nat Med. 2023 Feb 15.

mRNA vaccine effective against RSV respiratory disease.

Thiago Carvalho.

DOI: https://doi.org/10.1038/d41591-023-00017-7

Phytother Res. 2023 Feb 15.

Protective effect of saffron carotenoids against amyloid beta-induced neurotoxicity in differentiated PC12 cells via the unfolded protein response and autophagy.

Mariam Sanjari-Pour, Nassim Faridi, Ping Wang, S Zahra Bathaie.

The preventive effect of saffron against Alzheimer's disease (AD) has been reported. Herein, we studied the effect of Cro and Crt, saffron carotenoids, on the cellular model of AD. The MTT assay, flow cytometry, and elevated p-JNK, p-Bcl-2, and c-PARP indicated the AβOs-induced apoptosis in differentiated PC12 cells. Then, the protective effects of Cro/Crt on dPC12 cells against AβOs were investigated in preventive and therapeutic modalities. Starvation was used as a positive control. RT-PCR and Western blot results revealed the reduced eIF2α phosphorylation and increased spliced-XBP1, Beclin1, LC3II, and p62, which indicate the AβOs-induced autophagic flux defect, autophagosome accumulation, and apoptosis. Cro and Crt inhibited the JNK-Bcl-2-Beclin1 pathway. They altered Beclin1 and LC3II and decreased p62 expressions, leading cells to survival. Cro and Crt altered the autophagic flux by different mechanisms. So, Cro increased the rate of autophagosome degradation more than Crt, while Crt increased the rate of autophagosome formation more than Cro. The application of 4μ8C and chloroquine as the inhibitors of XBP1 and autophagy, respectively, confirmed these results. So, augmentation of the survival branches of UPR and autophagy is involved and may serve as an effective strategy to prevent the progression of AβOs toxicity.

Keywords: AD; AβOs; UPR; autophagy; crocetin; crocin

DOI: https://doi.org/10.1002/ptr.7773