bims-ershed 2022-12-18 papers

Issue of 2022‒12‒18
four papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

PLoS One. 2022 ;17(12): e0279016

Inositol-requiring enzyme 1α/X-box protein 1 pathway expression is impaired in pediatric cholestatic liver disease explants.

Alyssa Kriegermeier, Angela Hyon, Brian LeCuyer, Susan Hubchak, Xiaoying Liu, Richard M Green.

BACKGROUND: Increased intrahepatic bile acids cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, is associated with adult liver diseases but has not been characterized in pediatric liver diseases. We evaluated hepatic UPR expression in pediatric cholestatic liver disease (CLD) explants and hypothesize that an inability to appropriately activate the hepatic IRE1α/XBP1 pathway is associated with the pathogenesis of CLD.METHODS: We evaluated 34 human liver explants, including: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways.
RESULTS: Pathway analysis demonstrated that the KEGG 'protein processing in ER' pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1α/XBP1 pathway gene expression and decreased protein expression of phosphorylated IRE1α compared to normal controls. IRE1α/XBP1 pathway gene expression was also decreased in pediatric CLD compared to AIH disease controls.
CONCLUSIONS: Pediatric CLD explants have decreased expression of the protective IRE1α/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1α/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1α/XBP1 pathway is associated with cholestatic diseases and may be a target for future therapeutics.

DOI: https://doi.org/10.1371/journal.pone.0279016

Plants (Basel). 2022 Nov 22. pii: 3197. [Epub ahead of print]11(23):

ER Stress and the Unfolded Protein Response: Homeostatic Regulation Coordinate Plant Survival and Growth.

June-Sik Kim, Keiichi Mochida, Kazuo Shinozaki.

The endoplasmic reticulum (ER), a eukaryotic organelle, is the major site of protein biosynthesis. The disturbance of ER function by biotic or abiotic stress triggers the accumulation of misfolded or unfolded proteins in the ER. The unfolded protein response (UPR) is the best-studied ER stress response. This transcriptional regulatory system senses ER stress, activates downstream genes that function to mitigate stress, and restores homeostasis. In addition to its conventional role in stress responses, recent reports indicate that the UPR is involved in plant growth and development. In this review, we summarize the current knowledge of ER stress sensing and the activation and downstream regulation of the UPR. We also describe how the UPR modulates both plant growth and stress tolerance by maintaining ER homeostasis. Lastly, we propose that the UPR is a major component of the machinery that balances the trade-off between plant growth and survival in a dynamic environment.

Keywords: ER stress; defense; endoplasmic reticulum (ER); gene regulation; reproduction; stress response; unfolded protein response (UPR); vegetative growth

DOI: https://doi.org/10.3390/plants11233197

Int J Mol Sci. 2022 Dec 02. pii: 15186. [Epub ahead of print]23(23):

Endoplasmic Reticulum Stress Signaling and Neuronal Cell Death.

Adalberto Merighi, Laura Lossi.

Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca2+ homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.

Keywords: apoptosis; autophagy; cerebellar granule cells; endoplasmic reticulum; endoplasmic reticulum stress; unfolded protein response

DOI: https://doi.org/10.3390/ijms232315186

Curr Opin Pharmacol. 2022 Dec 13. pii: S1471-4892(22)00151-5. [Epub ahead of print]68 102324

Newly identified tumor suppressor functions of ING proteins.

Léane Heliez, Charles Ricordel, Philippe Becuwe, Rémy Pedeux.

The INhibitor of Growth (ING) proteins (ING1, ING2, ING3, ING4 and ING5) are a family of epigenetic regulators. Their decreased expression in numerous cancers led to identifying the ING proteins as gatekeeper tumor suppressors as they regulate cell cycle progression, apoptosis and senescence. Subsequently, they were also described as caretaker tumor suppressors through their involvement in DNA replication and the DNA damage response (DDR). Recent studies have identified new interactions of the ING proteins with proteins or pathways implicated in cell proliferation, the maintenance of stem cells pluripotency or the DDR. Furthermore, the ING proteins have been identified as regulators of ribosomal RNA synthesis and of mRNA stability and as regulators of mitochondrial DNA transcription resulting in the regulation of metabolism. These new findings highlight new antitumorigenic activities of the ING proteins that are potential targets for cancer treatment.

DOI: https://doi.org/10.1016/j.coph.2022.102324