Mevalonate Pathway-mediated ER Homeostasis Is Required for Haploid Stability in Human Somatic Cells

Yaguchi, Kan; Sato, Kimino; Yoshizawa, Koya; Mikami, Daisuke; Yuyama, Ken‐ichi; Igarashi, Yasuyuki; Bánhegyi, Gábor; Margittai, Éva; Uehara, Ritei

doi:10.1247/csf.20055

Cited by 2 publications

(2 citation statements)

References 45 publications

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“…We previously found that statin impaired the stability of the haploid state by evoking ER stress in a human haploid model cell line, HAP1 (9). However, the pleiotropic effects of mevalonate pathway suppression by statin precluded further investigation of a possible relationship between ploidy status and ER homeostatic controls.…”

Section: Er Stress Induction Aggravates Haploid Instability Through A...mentioning

confidence: 99%

“…A previous screening for compounds affecting haploid stability found 3-hydroxy-3-methylglutaryl-coA reductase (HMGCR) inhibitors statins to facilitate the haploid-to-diploid conversion of HAP1 cells (8). Statin-mediated haploid destabilization occurred not through cholesterol depletion, a primary downstream target of statins, but through evoking endoplasmic reticulum (ER) stress (9). However, the pleiotropic effects of statins on broad cellular processes precluded further investigation of the link between ER homeostatic control and haploid instability in human cells.…”

Section: Introductionmentioning

confidence: 99%

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Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells

Ishida-Ishihara,

Yaguchi,

Sato

et al. 2024

Preprint

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Mammalian somatic cells are generally unstable in the haploid state, resulting in haploid-to-diploid conversion within a short time frame. However, cellular and molecular principles that limit the sustainability of somatic haploidy remain unknown. In this study, we found the haploidy-linked vulnerability to ER stress as a critical cause of haploid intolerance in human somatic cells. Pharmacological induction of ER stress selectively induced apoptosis in haploid cells, facilitating the replacement of haploids by co-existing diploidized cells in a caspase-dependent manner. Biochemical analyses revealed that unfolded protein response (UPR) was activated with similar dynamics between haploids and diploids upon ER stress induction. However, haploids were less efficient in solving proteotoxic status, resulting in a bias toward a proapoptotic mode of UPR signaling. Artificial replenishment of chaperone function or inhibition of a UPR signal transducer ATF6 substantially alleviated the haploidy-linked upregulation of proapoptotic signaling and improved haploid cell retention under ER stress. These data demonstrate that the ER stress-driven haploid instability stems from inefficient proteostatic control that alters the functionality of UPR to cause apoptosis selectively in haploids. Interestingly, haploids suffered a higher level of protein aggregation even in unperturbed conditions, and the long-term stability of the haploid state was significantly improved by alleviating their natural proteotoxicity. Based on these results, we propose that the haploidy-specific vulnerability to ER stress creates a fundamental cause of haploid intolerance in mammalian somatic cells. Our findings provide new insight into the principle that places a stringent restriction on the evolution of animal life cycles.

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Section: Er Stress Induction Aggravates Haploid Instability Through A...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells

Ishida-Ishihara,

Yaguchi,

Sato

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells

Ishida-Ishihara,

Yaguchi,

Miura

et al. 2024

Journal of Biological Chemistry

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Mevalonate Pathway-mediated ER Homeostasis Is Required for Haploid Stability in Human Somatic Cells

Cited by 2 publications

References 45 publications

Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells

Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells

Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells

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