bims-cemest 2025-08-31 papers

Genes (Basel). 2025 Aug 13. pii: 957. [Epub ahead of print]16(8):

Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.

BACKGROUND: The mitochondrial integrated stress response (ISR) represents a fundamental cellular adaptation mechanism with dual protective and pathological roles. We critically analyzed current literature on ISR mechanisms, focusing on recent paradigm shifts including the 2020 discovery of the OMA1-DELE1-HRI axis, emerging controversies over context-dependent activation patterns, and the January 2025 clinical trial failures that have reshaped the therapeutic landscape.
METHODS: We reviewed recent literature (2020-2025) examining ISR mechanisms, clinical trials, and therapeutic developments through comprehensive database searches.
RESULTS: The field has evolved from simple linear pathway models to recognition of complex, context-dependent networks. Recent findings reveal that ISR activation mechanisms vary dramatically based on cellular metabolic state, with distinct pathways operating in proliferating versus differentiated cells. The "dark microglia" phenotype in neurodegeneration and DR5-mediated apoptotic switches exemplify pathological ISR manifestations, while adaptive responses include metabolic reprogramming and quality control enhancement.
CONCLUSIONS: The 2025 failures of DNL343 and ABBV-CLS-7262 in ALS trials underscore the need for precision medicine approaches that account for context-dependent ISR functions, temporal dynamics, and disease-specific mechanisms.

Keywords: cellular adaptation; eIF2α phosphorylation; integrated stress response; mitochondrial dysfunction; neurodegeneration; precision medicine

DOI: https://doi.org/10.3390/genes16080957

Curr Opin Cell Biol. 2025 Aug 22. pii: S0955-0674(25)00118-8. [Epub ahead of print]96 102580

Mechanisms of transmembrane domain recognition during endoplasmic reticulum quality control.

Nikita Sergejevs, Pedro Carvalho.

Misfolded proteins can be toxic to cells, and their accumulation is a hallmark of diseases such as neurodegeneration. Normally, protein homeostasis is maintained by quality control processes that eliminate misfolded proteins. In the endoplasmic reticulum (ER), misfolded proteins are eliminated through endoplasmic reticulum-associated degradation (ERAD). This process is mediated by ubiquitin ligase complexes that recognize substrates in the membrane and lumen of the ER and retrotranslocate them to the cytosol to mediate their ubiquitination for subsequent degradation by the proteasome. While the recognition of luminal substrates is well understood, how ERAD complexes specifically identify and select aberrant membrane proteins remains poorly defined. Here, we review examples of intramembrane substrate recognition during ERAD and discuss the principles involved.

DOI: https://doi.org/10.1016/j.ceb.2025.102580

Science. 2025 Aug 21. 389(6762): 782-783

A protein tunnel helps stressed lysosomes swell.

Jennifer Lippincott-Schwartz.

The endoplasmic reticulum donates lipids through a tunnel-like protein to help lysosomes expand.

DOI: https://doi.org/10.1126/science.aea5377

Nat Cell Biol. 2025 Aug 20.

Discovery of a multi-chaperone condensate in the endoplasmic reticulum.

DOI: https://doi.org/10.1038/s41556-025-01731-9

Nat Chem Biol. 2025 Aug 22.

α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.

The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment.

DOI: https://doi.org/10.1038/s41589-025-02013-z

Structure. 2025 Aug 20. pii: S0969-2126(25)00269-2. [Epub ahead of print]

Design of multi-target peptide modulators for protein chaperone networks.

Essential chaperones heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) collaborate in oncoprotein folding. Dual inhibition of these chaperones has shown synergy in preclinical studies but remains challenging to achieve. Using a computational approach, we designed peptides mimicking the predicted unfolding regions of Kinase CDK4, a client protein of both Hsp70 and Hsp90. Peptide Cdk4-2 is shown to simultaneously bind Hsp70, Hsp90, and co-chaperone Cdc37. Cdk4-2 is membrane permeable, inhibits CDK4-mediated retinoblastoma phosphorylation, and induces apoptosis in renal carcinoma cells. Structure-function studies identified a minimal pharmacophore for Hsp70 binding and critical interactions for peptide affinity. These findings demonstrate the feasibility of rationally designing multi-target modulators of chaperone networks. Cdk4-2 is a promising lead for therapeutic development, expanding the molecular space of modulators of cancer-associated multiprotein machineries. While focused on chaperones, the idea behind our strategy is general and immediately transferable to other multiprotein targets and networks.

Keywords: anticancer molecules; drug design; folding blockers; molecular dynamics; molecular recognition; oncogenes; protein degraders; protein folding; protein levels

DOI: https://doi.org/10.1016/j.str.2025.07.021

Cell Commun Signal. 2025 Aug 20. 23(1): 374

The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.

Jiayi E Wang, Charanya Muralidharan, Armando A Puente, Titli Nargis, Jacob R Enriquez, Ryan M Anderson, Raghavendra G Mirmira, Sarah A Tersey.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells. Macrophages infiltrate islets early in T1D pathogenesis, preceding the influx of T- and B-lymphocytes. The integrated stress response (ISR), a cellular pathway activated during stress, coordinates adaptive changes in gene expression to maintain cell function and survival. To study the ISR in macrophages, bone-marrow-derived macrophages were treated with a pharmacological inhibitor of the ISR (ISRIB) and polarized to a proinflammatory M1-like state. We observed a reduction in the number of proinflammatory macrophages, as well as a decrease in iNOS mRNA and protein levels, following ISRIB treatment. RNA-sequencing revealed a reduction in pathways related to stress responses, including ER stress, reactive oxygen species (ROS) regulation, and autophagy, as well as migration pathway genes. ISRIB treatment led to decreased macrophage migration after stimulation in vitro and reduced migration of macrophages to the site of injury after tailfin injury in zebrafish in vivo. Interestingly, ISRIB mediated reduction of M1-like macrophages and reduction of migration was recapitulated by the inhibition of PKR but not PERK, both upstream ISR kinases, highlighting PKR as a key mediator of the ISR in macrophages. Pre-diabetic female non-obese diabetic (NOD) mice administered ISRIB demonstrated an overall reduction in the macrophage numbers in the pancreatic islets. Additionally, the insulitic area of pancreata from ISRIB treated NOD mice had increased PD-L1 levels. PD-L1 protein but not mRNA levels were increased in M1-like macrophages after ISR and PKR inhibition. Our findings identify the ISR, particularly via PKR, as a critical regulator of macrophage driven inflammation and migration in T1D. Our study offers new insights into ISR signaling in macrophages, demonstrating that the ISR may serve as a potential target for intervention in macrophages during early T1D pathogenesis.

Keywords: Diabetes; Inflammation; Integrated stress response (ISR); Macrophages; Migration; Pancreatic islet; Unfolded protein response (UPR)

DOI: https://doi.org/10.1186/s12964-025-02372-z

FEBS Lett. 2025 Aug 25.

Biochemical mechanism of the mammalian circadian clock.

Yang Liu, Aziz Sancar.

Circadian rhythms, regulated by core clock proteins, coordinate physiological functions with daily environmental fluctuations across organisms, from bacteria to humans. The circadian clock interacts with various biological processes, and its disruption is associated with numerous human diseases, including sleep disorders, metabolic syndrome, and potentially cancer. In mammals, the circadian clock is driven by cell-autonomous transcription-translation feedback loops (TTFLs), in which CLOCK and BMAL1 act as transcriptional activators, while PER and CRY serve as transcriptional repressors. During the early repression phase, the CRY-PER-CK1 complex binds to CLOCK-BMAL1, displacing it from target promoters. In the late repression phase, in the absence of PER, CRY1 alone inhibits CLOCK-BMAL1 activity by blocking the recruitment of transcriptional coactivators. Biochemical and structural studies have highlighted the essential roles of protein-protein interactions, protein-DNA interactions, and posttranslational modifications in regulating the molecular clock. In this Review, we summarize the molecular mechanisms that govern the circadian clock and focus on the coordination of protein-protein interactions and posttranslational modifications, underscoring the importance of the circadian clock in disease progression and treatment strategies.

Keywords: cancer; circadian clock; cryptochromes; metabolic disease; posttranslational modification; protein–protein interaction; sleep disorder

DOI: https://doi.org/10.1002/1873-3468.70150