bims-ershed 2021-07-18 papers

Mol Cell Biochem. 2021 Jul 14.

Unfolded protein response during cardiovascular disorders: a tilt towards pro-survival and cellular homeostasis.

Shreya Das, Arunima Mondal, Jayeeta Samanta, Santanu Chakraborty, Arunima Sengupta.

The endoplasmic reticulum (ER) is an organelle that orchestrates the production and proper assembly of an extensive types of secretory and membrane proteins. Endoplasmic reticulum stress is conventionally related to prolonged disruption in the protein folding machinery resulting in the accumulation of unfolded proteins in the ER. This disruption is often manifested due to oxidative stress, Ca2+ leakage, iron imbalance, disease conditions which in turn hampers the cellular homeostasis and induces cellular apoptosis. A mild ER stress is often reverted back to normal. However, cells retaliate to acute ER stress by activating the unfolded protein response (UPR) which comprises three signaling pathways, Activating transcription factor 6 (ATF6), inositol requiring enzyme 1 alpha (IRE1α), and protein kinase RNA-activated-like ER kinase (PERK). The UPR response participates in both protective and pro-apoptotic responses and not much is known about the mechanistic aspects of the switch from pro-survival to pro-apoptosis. When ER stress outpaces UPR response then cell apoptosis prevails which often leads to the development of various diseases including cardiomyopathies. Therefore, it is important to identify molecules that modulate the UPR that may serve as promising tools towards effective treatment of cardiovascular diseases. In this review, we elucidated the latest advances in construing the contribution imparted by the three arms of UPR to combat the adverse environment in the ER to restore cellular homeostasis during cardiomyopathies. We also summarized the various therapeutic agents that plays crucial role in tilting the UPR response towards pro-survival.

Keywords: Cardioprotective; Cardiovascular diseases; Chemical; ER stress; Natural products; Unfolded protein response

DOI: https://doi.org/10.1007/s11010-021-04223-0

RNA. 2021 Jul 08. pii: rna.078858.121. [Epub ahead of print]

Recruitment of endoplasmic reticulum-targeted and cytosolic mRNAs into membrane-associated stress granules.

Jessica Rae Child, Qiang Chen, David W Reid, Sujatha Jagannathan, Christopher Nicchitta.

Stress granules (SGs) are membraneless organelles composed of mRNAs and RNA binding proteins which undergo assembly in response to stress-induced inactivation of translation initiation. In general, SG recruitment is limited to a subpopulation of a given mRNA species and RNA-seq analyses of purified SGs revealed that signal sequence-encoding (i.e. endoplasmic reticulum (ER)-targeted) transcripts are significantly under-represented, consistent with prior reports that ER localization can protect mRNAs from SG recruitment. Using translational profiling, cell fractionation, and single molecule mRNA imaging, we examined SG biogenesis following activation of the unfolded protein response (UPR) by 1,4-dithiothreitol (DTT) and report that gene-specific subsets of cytosolic and ER-targeted mRNAs can be recruited into SGs. Furthermore, we demonstrate that SGs form in close proximity to or directly associated with the ER membrane. ER-associated SG assembly was also observed during arsenite stress, suggesting broad roles for the ER in SG biogenesis. Recruitment of a given mRNA into SGs required stress-induced translational repression, though translational inhibition was not solely predictive of an mRNA's propensity for SG recruitment. SG formation was prevented by the transcriptional inhibitors actinomycin D or triptolide, suggesting a functional link between gene transcriptional state and SG biogenesis. Collectively these data demonstrate that ER-targeted and cytosolic mRNAs can be recruited into ER-associated SGs and this recruitment is sensitive to transcriptional inhibition. We propose that newly transcribed mRNAs exported under conditions of suppressed translation initiation are primary SG substrates, with the ER serving as the central subcellular site of SG formation.

Keywords: endoplasmic reticulum; mRNA; stress granule; translational regulation; unfolded protein response

DOI: https://doi.org/10.1261/rna.078858.121

J Physiol. 2021 Jul 16.

Excessive endoplasmic reticulum stress drives aberrant mouse trophoblast differentiation and placental development leading to pregnancy loss.

Nadejda Capatina, Myriam Hemberger, Graham J Burton, Erica D Watson, Hong Wa Yung.

Endoplasmic reticulum (ER) stress promotes placental dysmorphogenesis and is associated with poor pregnancy outcomes. We show that unfolded protein response signalling pathways located in the ER drive differentiation of mouse trophoblast stem cells into trophoblast subtypes involved in development of the placental labyrinth zone and trophoblast invasion. In a mouse model of chronic ER stress (Eif2s1tm1RjK ), higher ER stress in homozygous blastocysts is accompanied by reduced trophectoderm cell number, developmental delay, and is associated with an increased incidence of early pregnancy loss. Administration of the chemical chaperone, tauroursodeoxycholic acid, to Eif2s1tm1RjK heterozygous females during pregnancy alleviated ER stress in the mutant placenta, restored normal trophoblast populations and reduced the frequency of early pregnancy loss. Our results suggest that alleviation of intrauterine ER stress could provide a potential therapeutic target to improve pregnancy outcome in women with pre-gestational metabolic or gynaecologic conditions. ABSTRACT: Women with pre-gestational health conditions (e.g., obesity, diabetes) or gynaecological problems (e.g., endometriosis) are at increased risk of adverse pregnancy outcomes including miscarriage, preeclampsia and fetal growth restriction. Increasing evidence suggests that unfavourable intrauterine conditions leading to poor implantation and/or defective placentation are a possible causative factor. The endoplasmic reticulum (ER) unfolded protein response (UPRER ) signalling pathways are a convergence point of various physiological stress stimuli that can be triggered by an unfavourable intrauterine environment. Therefore, we explored the impact of ER stress on mouse trophoblast differentiation in vitro, mouse blastocyst formation and early placenta development in the Eif2s1tm1RjK mutant mouse model of chronic ER stress. Chemically-manipulated ER stress or activation of UPRER pathways in a mouse trophoblast stem cell line promoted lineage-specific differentiation. Co-treatment with specific UPRER pathway inhibitors rescued this effect. While the inner cell mass was unaffected, the trophectoderm of homozygous Eif2s1tm1RjK blastocysts exhibited ER stress associated with a reduced cell number. Furthermore, one-third of Eif2s1tmRjK homozygous blastocysts exhibited severe developmental defects. We have previously reported a reduced trophoblast population and premature trophoblast differentiation in Eif2s1tm1RjK homozygous placentas at mid-gestation. Here, we demonstrate that treatment of Eif2s1+/tm1RjK heterozygous pregnant females with the chemical chaperone tauroursodeoxycholic acid alleviated ER stress, restored the trophoblast population, and reduced the frequency of embryonic lethality. Our data suggest that therapeutic targeting of ER stress may improve pregnancy outcome in women with pre-gestational metabolic or gynaecologic conditions. This article is protected by copyright. All rights reserved.

Keywords: Endoplasmic reticulum stress; Placental development; Pregnancy complications; Trophoblast differentiation

DOI: https://doi.org/10.1113/JP281994

Dev Biol. 2021 Jul 12. pii: S0012-1606(21)00171-8. [Epub ahead of print]

The role of Ire1 in Drosophila eye pigmentation revealed by an RNase dead allele.

Sahana Mitra, Hyung Don Ryoo.

Ire1 is an endoplasmic reticulum (ER) transmembrane RNase that cleaves substrate mRNAs to help cells adapt to ER stress. Because there are cell types with physiological ER stress, loss of Ire1 results in metabolic and developmental defects in diverse organisms. In Drosophila, Ire1 mutants show developmental defects at early larval stages and in pupal eye photoreceptor differentiation. These Drosophila studies relied on a single Ire1 loss of function allele with a Piggybac insertion in the coding sequence. Here, we report that an Ire1 allele with a specific impairment in the RNase domain, H890A, unmasks previously unrecognized Ire1 phenotypes in Drosophila eye pigmentation. Specifically, we found that the adult eye pigmentation is altered, and the pigment granules are compromised in Ire1H890A homozygous mosaic eyes. Furthermore, the Ire1H890A mutant eyes had dramatically reduced Rhodopsin-1 protein levels. Drosophila eye pigment granules are most notably associated with late endosome/lysosomal defects. Our results indicate that the loss of Ire1, which would impair ER homeostasis, also results in altered adult eye pigmentation.

Keywords: , Pigment granules; Drosophila; Ire1; RNase; Rhodopsin-1

DOI: https://doi.org/10.1016/j.ydbio.2021.07.008

Aust N Z J Public Health. 2021 Jul 12.

COVID-19 as a context in suicide: early insights from Victoria, Australia.

Justin Dwyer, Jeremy Dwyer, Richard Hiscock, Clare O'Callaghan, Keryn Taylor, Ciara Millar, Ashne Lamb, Lyndal Bugeja.

OBJECTIVE: To examine how the coronavirus (COVID-19) pandemic and its consequences may have influenced suicide in Victoria, Australia.
METHODS: A mixed methods study of consecutive Victorian suicide cases spanning 1 January 2015 to 31 January 2021. Interrupted time series analysis examined whether suicide frequency changed following the pandemic onset. Thematic analysis was undertaken of police reports in suicides linked with COVID-19 to try to understand how COVID-19 acted as a stressor.
RESULTS: The frequency of Victorian suicides did not change following the onset of COVID-19. Sixty COVID-linked suicides were identified, featuring three recurring themes: COVID-19 as a disturbance in the self, in relationships with others and institutions.
CONCLUSIONS: While COVID-19 has not led to an increase in Victorian suicide frequency to date, it is an important background stressor that can erode one's wellbeing, sense of agency and connectedness to others. Implications for public health: Clinical interventions that serve to reconnect people with a sense of agency and seek to re-establish contact with significant others are indicated. Clinicians should ensure they are familiar with pathways for their patients to access government social and economic supports. A better understanding of how government interventions may be lessening psychological distress is needed.

Keywords: COVID-19; mixed-methods; suicide

DOI: https://doi.org/10.1111/1753-6405.13132