The generation of new cells is one of the most fundamental aspects of cell biology. Proper regulation of the cell cycle is critical for human health, as underscored by many diseases associated with errors in cell cycle regulation, including both cancer and hereditary diseases. A large body of work has identified regulatory mechanisms and checkpoints that ensure accurate and timely replication and segregation of chromosomal DNA. However, few studies have evaluated the extent to which similar checkpoints exist for the division of cytoplasmic components, including organelles. Such checkpoint mechanisms might be crucial for compartments that cannot be generated de novo, such as the endoplasmic reticulum (ER). In this review, we highlight recent work in the model organism Saccharomyces cerevisiae that led to the discovery of such a checkpoint that ensures that cells inherit functional ER into the daughter cell.

When the novel coronavirus SARS-CoV-2 infects human cells, it results in the formation of “double-membrane vesicles” (DMVs) upon major rearrangements of the host cell compartment called the endoplasmic reticulum (ER) (Cortese et al., 2020). Previous studies have identified that nonstructural protein 4 (Nsp4), one of SARS-CoV-2 coded proteins, is involved in formation of the DMVs in mammalian cells (Angelini et al., 2013; Hagemeijer et al., 2014; Oudshoorn et al., 2017). Importantly without proper DMV formation, SARS-CoV are unable to replicate and reproduce in the infected cell (Sakai et al., 2017). Little is known about if host cell components are involved and the molecular mechanisms by which the DMV is formed. In order to answer these questions, we used a minimal experimental model and transformed a plasmid that expresses SARS-CoV-2 Nsp4 under the galactose regulatable promoter into wild type Saccharomyces cerevisiae, or budding yeast. These cells carried a prominent ER transmembrane protein fused with GFP (Pho88-GFP) integrated in the genomic pho88 locus. Here, we show that expression of Nsp4 alone in WT cells results in the dramatic rearrangement of ER structure. Using gene knockout cell strains, we found that while upstream elements of ER stress mitigating pathways like the unfolded protein response (UPR) and ER stress surveillance (ERSU) checkpoint were not involved in these rearrangements, proteins Vps4 and Vps24 of the endosomal sorting complexes required for transport (ESCRT) were involved. Finally, we discovered that inducing Nsp4 expression results in a significant decrease of ER inheritance into the daughter cell and is mediated in part by Vps4. This minimal experimental approach allows for a further investigation of host components involved in both morphological and functional changes of the ER and potential drug targets to disrupt DMVs, and thus SARS-CoV-2 reproduction.

Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress and acquired cardiomyopathy remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy. We also found that DELE1 cKO mice exhibit similar cardiac structure and function, compared with controls, in response to pressure overload-induced heart failure.

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