bims-ershed 2023-01-15 papers

Issue of 2023‒01‒15
three papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

Cell Chem Biol. 2022 Dec 31. pii: S2451-9456(22)00454-8. [Epub ahead of print]

Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.

Shuhong Sun, Chao Wang, Pei Zhao, Gabe M Kline, Julia M D Grandjean, Xin Jiang, Richard Labaudiniere, R Luke Wiseman, Jeffery W Kelly, William E Balch.

Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and function at a residue-by-residue level by pharmacological activation of the ATF6 arm of the unfolded protein response (UPR). We show that ATF6 activators increase AAT neutrophil elastase (NE) inhibitory activity, while reducing polymer accumulation for the majority of AATD variants, including the prominent Z variant. GP-based profiling of the residue-by-residue response to ATF6 activators captures an unexpected role of the "gate" area in managing AAT-specific activity. Our work establishes a new spatial covariant (SCV) understanding of the convertible state of the protein fold in response to genetic perturbation and active environmental management by proteostasis enhancement for precision medicine.

Keywords: Gaussian process; activating transcription factor 6 (ATF6); alpha-1 antitrypsin; alpha-1 antitrypsin deficiency; chaperones; genetic variation; machine learning; pharmacological ATF6 activators; precision medicine; protein aggregation; protein folding; protein misfolding disease; proteostasis; unfolded protein response (UPR)

DOI: https://doi.org/10.1016/j.chembiol.2022.12.004

Int J Mol Sci. 2022 Dec 29. pii: 577. [Epub ahead of print]24(1):

Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR).

Gehan Botrus, Richard M Miller, Pedro Luiz Serrano Uson Junior, Geoffrey Kannan, Haiyong Han, Daniel D Von Hoff.

High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1α, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death.

Keywords: apoptosis; endoplasmic reticulum (ER) stress; pancreatic cancer; unfolded protein response (UPR)

DOI: https://doi.org/10.3390/ijms24010577

Biochem Soc Trans. 2023 Jan 11. pii: BST20211187. [Epub ahead of print]

CD95/Fas ligand induced toxicity.

Ashley Haluck-Kangas, Marcus E Peter.

The role of CD95/Fas ligand (CD95L/FasL) in the induction of CD95-mediated extrinsic apoptosis is well characterized. Trimerized, membrane-bound CD95L ligates the CD95 receptor activating downstream signaling resulting in the execution of cells by caspase proteins. However, the expression of CD95L has been reported to induce cell death in contexts in which this pathway is unlikely to be activated, such as in cell autonomous activation induced cell death (AICD) and in CD95-resistant cancer cell lines. Recent data suggests that the CD95L mRNA exerts toxicity through death induced by survival gene elimination (DISE). DISE results from the targeting of networks of survival genes by toxic short RNA (sRNA)s in the RNA-induced silencing complex (RISC). CD95L mRNA contributes to this death directly, through the processing of its mRNA into toxic sRNAs that are loaded into the RISC, and indirectly, by promoting the loading of other toxic sRNAs. Interestingly, CD95L is not the only mRNA that is processed and loaded into the RISC. Protein-coding mRNAs involved in protein translation are also selectively loaded. We propose a model in which networks of mRNA-derived sRNAs modulate DISE, with networks of genes providing non-toxic RISC substrate sRNAs that protect against DISE, and opposing networks of stress-activated genes that produce toxic RISC substrate sRNAs that promote DISE.

Keywords: DISE; FasL; RISC; RNA toxicity; RNAi; cell death

DOI: https://doi.org/10.1042/BST20211187