bims-ershed 2021-09-19 papers

Issue of 2021‒09‒19
nine papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

J Am Heart Assoc. 2021 Sep 17. e020441

Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of ApoE-/- Mice.

Yuxiang Zhou, Xueping Wan, Kerstin Seidel, Mo Zhang, Jena B Goodman, Francesca Seta, Naomi Hamburg, Jingyan Han.

Background Persistent activation of endoplasmic reticulum stress and the unfolded protein response (UPR) induces vascular cell apoptosis, contributing to atherogenesis. Aging and hypercholesterolemia are 2 independent proatherogenic factors. How they affect vascular UPR signaling remains unclear. Methods and Results Transcriptome analysis of aortic tissues from high fat diet-fed and aged ApoE-/- mice revealed 50 overlapping genes enriched for endoplasmic reticulum stress- and UPR-related pathways. Aortae from control, Western diet (WD)-fed, and aged ApoE-/- mice were assayed for (1) 3 branches of UPR signaling (pancreatic ER eIF2-alpha kinase /alpha subunit of the eukaryotic translation initiation factor 1/activating transcription factor 4, inositol-requiring enzyme 1 alpha/XBP1s, activating transcription factor 6); (2) UPR-mediated protective adaptation (upregulation of immunoglobulin heavy chain-binding protein and protein disulfide isomerase); and (3) UPR-mediated apoptosis (induction of C/EBP homologous transcription factor, p-JNK, and cleaved caspase-3). Aortic UPR signaling was differentially regulated in the aged and WD-fed groups. Consumption of WD activated all 3 UPR branches; in the aged aorta, only the ATF6α arm was activated, but it was 10 times higher than that in the WD group. BiP and protein disulfide isomerase protein levels were significantly decreased only in the aged aorta despite a 5-fold increase in their mRNA levels. Importantly, the aortae of aged mice exhibited a substantially enhanced proapoptotic UPR compared with that of WD-fed mice. In lung tissues, UPR activation and the resultant adaptive/apoptotic responses were not significantly different between the 2 groups. Conclusions Using a mouse model of atherosclerosis, this study provides the first in vivo evidence that aging and an atherogenic diet activate differential aortic UPR pathways, leading to distinct vascular responses. Compared with dietary intervention, aging is associated with impaired endoplasmic reticulum protein folding and increased aortic apoptosis.

Keywords: aging; apoE deficient mice; hypercholesterolemia; unfolded protein response; vascular cells

DOI: https://doi.org/10.1161/JAHA.120.020441

MicroPubl Biol. 2021 ;2021

Daughter cell-targeted mRNAs can achieve segregation without the universal Endoplasmic Reticulum docker She2p.

Kseniya Samardak, María Moriel-Carretero.

The establishment of cell polarity in eukaryotes involves the asymmetric distribution of messenger RNAs (mRNAs). In Saccharomyces cerevisiae, establishment of the cell polarity that gives rise to mother and daughter cells concurs with the selective targeting of more than 30 mRNAs toward the bud tip. Different mRNAs are segregated at different cell cycle stages, namely early during S phase, in a process dependent on anchoring to the endoplasmic reticulum (ER), or later in G2 or mitosis, in an ER-independent manner. In spite of this difference, this transport requires in all cases the Myo4p motor and its interaction with actin, the adaptor protein She3p and a third, RNA-binding protein docking this complex at the mRNA itself. This protein is universally considered to be She2p. Yet, the majority of mRNAs whose segregation was shown to be She2p-dependent are not S-phase segregated ones. In other processes aimed at establishing polarity, such as during pheromone-stimulated G1 arrest, the coupling of mRNAs to the ER during their transport is She2p-independent. We have therefore asked if the segregation to the bud of a model S-phase-specific mRNA, EAR1, is dependent on She2p or not. We report that a modest yet consistent percentage of EAR1 segregating particles achieves polarization without She2p. Our data invite to a re-evaluation of the absolute necessity for She2p for daughter cell-targeted mRNAs distribution.

DOI: https://doi.org/10.17912/micropub.biology.000458

J Biol Chem. 2021 Sep 09. pii: S0021-9258(21)00986-8. [Epub ahead of print] 101184

The deubiquitinating enzyme USP37 enhances CHK1 activity to promote the cellular response to replication stress.

Benjamin R Stromberg, Mayank Singh, Adrian E Torres, Amy C Burrows, Debjani Pal, Christine Insinna, Yosup Rhee, Andrew S Dickson, Christopher J Westlake, Matthew K Summers.

The deubiquitinating enzyme USP37 is known to contribute to timely onset of S-phase and progression of mitosis. However, it is not clear if USP37 is required beyond S-phase entry despite expression and activity of USP37 peaking within S-phase. We have utilized flow cytometry and microscopy to analyze populations of replicating cells labeled with thymidine analogs and monitored mitotic entry in synchronized cells to determine that USP37-depleted cells exhibited altered S-phase kinetics. Further analysis revealed that cells depleted of USP37 harbored increased levels of the replication stress and DNA damage markers γH2AX and 53BP1 in response to perturbed replication. Depletion of USP37 also reduced cellular proliferation and led to increased sensitivity to agents that induce replication stress. Underlying the increased sensitivity, we found that the checkpoint kinase CHK1 is destabilized in the absence of USP37, attenuating its function. We further demonstrated that USP37 deubiquitinates CHK1, promoting its stability. Together our results establish that USP37 is required beyond S-phase entry to promote the efficiency and fidelity of replication. These data further define the role of USP37 in the regulation of cell proliferation and contribute to an evolving understanding of USP37 as a multifaceted regulator of genome stability.

Keywords: CHK1; DNA damage response; DNA replication; USP37; cell cycle; checkpoint control; deubiquitination; ubiquitination

DOI: https://doi.org/10.1016/j.jbc.2021.101184

MicroPubl Biol. 2021 ;2021

Decreased Mitochondrial Membrane Potential Activates the Mitochondrial Unfolded Protein Response.

Brandon J Berry, Tyrone O Nieves, Andrew P Wojtovich.

Mitochondria are ATP-producing organelles that also signal throughout the cell. Mitochondrial protein homeostasis is regulated through membrane potential-dependent protein import and quality control signaling. The mitochondrial unfolded protein response (UPRmt) is a specific program that responds to imbalances in nuclear and mitochondrial gene expression. Mounting evidence suggests that the electrochemical gradient that powers mitochondrial function, the mitochondrial membrane potential (Δψm), is a core regulator of the UPRmt. Here we tested this notion directly by pharmacologically dissipating Δψm and monitoring UPRmt activation. We found that chemical dissipation of Δψm using FCCP indeed activated UPRmt dose-dependently in C. elegans assayed by the HSP-60::GFP reporter strain.

DOI: https://doi.org/10.17912/micropub.biology.000445

J Exp Clin Cancer Res. 2021 Sep 14. 40(1): 289

The non-canonical mechanism of ER stress-mediated progression of prostate cancer.

BACKGROUND: The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation.METHODS: Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy.
RESULTS: Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites.
CONCLUSIONS: We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.

Keywords: Alcohol abuse; ER stress; Golgi fragmentation; Prostate cancer

DOI: https://doi.org/10.1186/s13046-021-02066-7

Nature. 2021 09;597(7876): 318-324

The tangled history of mRNA vaccines.

Elie Dolgin.

Keywords: History; Intellectual-property rights; SARS-CoV-2; Vaccines

DOI: https://doi.org/10.1038/d41586-021-02483-w

Brain Behav Immun Health. 2021 Oct;16 100323

Can (immune and other) gene expression help us to treat depression?

Nicole Mariani.

It is becoming clearer that it might be a combination of different biological processes such as genetic, environmental, and psychological factors, together with immune system, stress response, brain neuroplasticity and the regulation of neurotransmitters, that leads to the development of major depressive disorder (MDD). A growing number of studies have tried to investigate the underlying mechanisms of MDD by analysing the expression levels of genes (mRNA) involved in such biological processes. In this review, I have highlighted a possible key role that gene expression might play in the treatment of MDD. This is critical because many patients do not respond to antidepressant treatment or can experience side effects, causing treatment to be interrupted. Unfortunately, selecting the best antidepressant for each individual is still largely a matter of making an informed guess.

Keywords: Depression; Gene expression; Treatment response

DOI: https://doi.org/10.1016/j.bbih.2021.100323

Biomaterials. 2021 Sep 12. pii: S0142-9612(21)00486-5. [Epub ahead of print]277 121129

Expanding the toolbox of exosome-based modulators of cell functions.

Qinqin Cheng, Zhefu Dai, Xiaojing Shi, Xinping Duan, Yiling Wang, Tianling Hou, Yong Zhang.

Exosomes are cell-derived extracellular vesicles and play important roles in mediating intercellular communications. Due to their unique advantages in transporting a variety of biomolecules, exosomes have been emerging as a new class of nanocarriers with great potential for therapeutic applications. Despite advancements in loading chemotherapeutics and interfering RNAs into exosomes, active incorporation of protein molecules into exosomes remains challenging owing to their distinctive physicochemical properties and/or a lack of knowledge of cargo sorting during exosome biogenesis. Here we report the generation of a novel type of engineered exosomes with actively incorporated membrane proteins or soluble protein cargos, named genetically infused functionally tailored exosomes (GIFTed-Exos). Through genetic fusion with exosome-associated tetraspanin CD9, transmembrane protein CD70 and glucocorticoid-induced tumor necrosis factor receptor family-related ligand (GITRL) could be displayed on exosome surface, resulting in GIFTed-Exos with excellent T-cell co-stimulatory activities. By genetically linking to a CD9-photocleavable protein fusion, fluorescent protein mCherry, apoptosis-inducing protein apoptin, and antioxidant enzyme catalase could be effectively packed into exosomes for light-controlled release. The generated GIFTed-Exos display notable in vitro and in vivo activities for delivering distinct types of protein cargos to target cells. As a possibly general approach, GIFTed-Exos provide new opportunities to create exosomes with new functions and properties for biomedical research.

Keywords: Drug delivery; Exosomes; Nanotechnology; Protein engineering; Synthetic biology

DOI: https://doi.org/10.1016/j.biomaterials.2021.121129