bims-cemest 2025-06-15 papers

iScience. 2025 Jun 20. 28(6): 112569

Impact of ATF6 deletion on the embryonic brain development.

Loc Dinh Nguyen, Ly Huong Nguyen, Dat Xuan Dao, Tsuyoshi Hattori, Mika Takarada-Iemata, Hiroshi Ishii, Takashi Tamatani, Hiroshi Kawasaki, Yohei Shinmyo, Kenta Onoue, Shigenobu Yonemura, Jun Zhang, Masato Miyake, Seiichi Oyadomari, Kazutoshi Mori, Osamu Hori.

Although the unfolded protein response (UPR) is activated during brain development, its roles remain unclear. Here, we report that deletion of activating transcription factor 6 (ATF6), consisting of ATF6α and ATF6β, in the developing brain caused microcephaly and neonatal death in mice. Analysis of Atf6a/Atf6b double conditional knockout (dcKO) brains revealed diverse neuronal phenotypes, such as reduced neurogenesis, increased cell death, impaired cortical layer formation, and axon projection defects. Furthermore, hypervasculature, glial defects, and neuroinflammation were observed in dcKO brains. Notably, hypervasculature was detected at E14.5, when endoplasmic reticulum (ER) stress was morphologically unclear, but the UPR was activated to a greater extent in dcKO brains. Expression profiles revealed reduced levels of molecular chaperones in the ER and enhanced levels of PERK- and IRE1-downstream molecules, including VEGFA, in dcKO brains. Administration of a chemical chaperone 4-phenylbutyric acid partially rescued dcKO mice, suggesting roles of ATF6 for improving proteostasis and for coordinating the UPR.

Keywords: Cell biology; Developmental biology; Neuroscience

DOI: https://doi.org/10.1016/j.isci.2025.112569

Trends Biochem Sci. 2025 Jun 11. pii: S0968-0004(25)00108-2. [Epub ahead of print]

Proteostasis in cellular dormancy: lessons from yeast to oocytes.

Stephanie Rosswag de Souza, Elvan Böke, Gabriele Zaffagnini.

Cellular dormancy is characterized by a prolonged, reversible cell cycle arrest and absence of growth. Dormancy allows organisms to endure unfavorable environmental conditions and to maintain long-lived quiescent progenitor cells essential for tissue homeostasis and reproduction. Protein homeostasis (proteostasis) is central to the maintenance of intracellular integrity in all cell types, particularly in long-lived, non-dividing cells. Here we review adaptations to support proteostasis in dormant cells and highlight common themes of cellular dormancy across organisms, from yeast to adult quiescent stem cells. We also feature vertebrate oocytes as an emerging model of proteostasis during dormancy. Together, these comparisons reveal common and unique strategies to sustain proteostasis during dormancy, offering insights into how cells preserve function and viability over long quiescence periods.

Keywords: mTOR; protein aggregates; protein degradation; quiescence; ribosome biogenesis; translation

DOI: https://doi.org/10.1016/j.tibs.2025.05.004

Adv Sci (Weinh). 2025 Jun 11. e00233

Organization of the Proteostasis Network of Membraneless Organelles.

Christine M Lim, Yuqi Bian, Alicia González Díaz, Frank Pun, Alex Zhavoronkov, Richard I Morimoto, Michele Vendruscolo.

Membraneless organelles (MLOs) are dynamic macromolecular condensates that act as crucibles to modulate cellular processes. Since MLOs form in the absence of lipid membranes, it is important to understand how their effective regulation is achieved by the protein homeostasis (proteostasis) system. To address this question, a comprehensive mapping of the proteostasis network (PN) of MLOs, comprising over 220 000 protein-protein interactions is reported. This analysis reveals how regulatory proteins (PN proteins) occupy central roles in the overall protein-protein interaction network of MLOs. It is then investigated which branches of the PN are most important in the regulation of MLOs, finding that the anabolic component, which makes up ≈30% of the PN, is more closely involved than the catabolic component, which makes up the remaining ≈70% of the PN. It is also found that translation-related PN proteins and molecular chaperones play central roles in MLO regulation. Finally, how specificity may be achieved despite shared PN components is explored. These findings suggest that HSP70 chaperones function as generic MLO regulators, while client-specific HSP70 co-chaperones confer specificity to the chaperone action. These results identify the composition of the PN of MLOs, rationalize its organization, and reveal central roles of molecular chaperones in protein regulation within MLOs.

Keywords: liquid‐liquid phase separation; membraneless organelles; protein condensation; protein homeostasis

DOI: https://doi.org/10.1002/advs.202500233

Curr Opin Genet Dev. 2025 Jun 06. pii: S0959-437X(25)00059-0. [Epub ahead of print]93 102367

mRNA translational control of regeneration.

Mehdi Amiri, Nahum Sonenberg, Soroush Tahmasebi.

mRNA translation is rapidly upregulated after injury to supply proteins required for tissue regeneration. Augmented protein synthesis during regeneration has long been associated with increases in ribosome biogenesis and mTORC1 activity. Emerging evidence highlights the roles of multiple signaling pathways, RNA-binding proteins, and RNA modifications in tissue repair. Here, we review recent research on the molecular mechanisms underlying translational control in response to tissue damage. The findings underscore the importance of mRNA translation in regeneration and its potential therapeutic applications in tissue repair.

DOI: https://doi.org/10.1016/j.gde.2025.102367

iScience. 2025 Jun 20. 28(6): 112605

Effect of glycosylation on protein folding: From biological roles to chemical protein synthesis.

Chunchun Hao, Qijie Zou, Xuerong Bai, Weiwei Shi.

Chemical protein synthesis has become an important tool in biotechnology and synthetic biology for producing proteins with complex structures. However, achieving correct folding in vitro remains a significant challenge. Glycosylation, a ubiquitous modification, stabilizes folding intermediates, prevents aggregation, and accelerates folding in both cellular and cell-free systems. In this review, we discuss the dual role of glycosylation in biological systems and in vitro experiments, focusing on how it promotes protein folding and stability. We also discuss the temporary glycosylation scaffold strategy for chemical protein synthesis, which offers a reversible approach to guide protein folding without leaving permanent modifications. This strategy provides a promising solution to the challenges of in vitro folding and holds significant potential to produce therapeutic proteins and the development of synthetic proteins with precise structural requirements.

Keywords: Biological sciences; Chemistry; Protein

DOI: https://doi.org/10.1016/j.isci.2025.112605

Nat Rev Drug Discov. 2025 Jun 09.

Targeting protein disorder: the next hurdle in drug discovery.

Tamas Lazar, Acadia Connor, Charles F DeLisle, Virginia Burger, Peter Tompa.

Intrinsically disordered proteins have key signalling and regulatory roles in cells and are frequently dysregulated in diseases such as cancer, neurodegeneration, inflammation and autoimmune disorders. Preventing the pathological functions mediated by structural disorder is crucial to successfully target proteins that drive transcription, biomolecular condensation and protein aggregation. However, owing to their heterogeneous, highly dynamic structural states, with ensembles of rapidly interconverting conformations, disordered proteins have been considered largely 'undruggable' by traditional approaches. Here, we review key developments of the field and suggest that the synergy of advanced experimental and computational approaches needs to be pursued to conquer this barrier in drug discovery.

DOI: https://doi.org/10.1038/s41573-025-01220-6