The PRECISE European initiative for cancer-vulnerability mapping and prediction

Francesco Iorio ^{#  1} , Mathew J Garnett ^{#  2} , Pedro Beltrao  ³ , Maximilian Billmann  ⁴ , Larissa Bless  ⁵ , Christoph Bock  ^{6   7} , Michael Boutros  ⁸ , Alejandra Bruna  ^{9   10} , Piero Carninci  ^{11   12} , Giovanni Ciriello  ¹³ , Isidro Cortés-Ciriano  ^{14   15} , Giuseppina D’Alessandro  ¹⁶ , Roberta Esposito  ^{17   18} , Stefania Faletti  ¹¹ , Emanuel Gonçalves  ^{19   20} , Syed Haider  ²¹ , Nereo Kalebic  ¹¹ , Manuel Kaulich  ^{22   23} , Giuseppe Leuzzi  ¹⁶ , Nuria Lopez-Bigas  ^{24   25   26} , Christopher J Lord  ²¹ , Evangelia Petsalaki  ^{15   27} , Stephen Pettitt  ²¹ , Ludovica Proietti  ¹¹ , Roland Rad  ^{28   29} , Nevenka Radic  ¹¹ , Colm J Ryan  ^{30   31} , Jonathan L Schmid-Burgk  ³² , Sumana Sharma  ³³ , Andrea Sottoriva  ¹¹ , Christopher Tape  ³⁴ , Livio Trusolino  ^{35   36} , Jolanda van Leeuwen  ^{37   38} , David Walter  ³⁹ , Lodewyk Wessels  ^{40   41} ; PRECISE consortium

Affiliations

• PMID: 42432245
• DOI: 10.1038/s41588-026-02658-z

No abstract available

Role of Pbr1, a putative oxidoreductase, in the ER quality control and folding of yeast Fks1 glucan synthase

Keisuke Obara ^{#  1} , Hiroki Okada ^{#  2   3} , Guihong Tan ^{#  4} , Shinsuke Ohnuki  ² , Godai Suzuki  ² , Haruka Ohtake  ² , Karen Kubo  ² , Farzan Ghanegolmohammadi  ² , Shunsuke Ishizaka  ² , Yoko Yashiroda  ⁵ , Aoi Okita  ¹ , Emi Mishiro-Sato  ⁶ , Kuninori Suzuki  ² , Yasushi Tamura  ⁷ , Rei Ashine  ⁸ , Yoshiki Ikeda  ⁸ , Takumi Kamura  ¹ , Jolanda van Leeuwen  ^{9   10} , Brenda Andrews  ⁴ , Erfei Bi  ³ , Nobuo N Noda  ¹¹ , Charles Boone  ^{4   5} , Yoshikazu Ohya  ^{2   12   13}

Affiliations

• PMID: 42441850
• DOI: 10.1073/pnas.2612792123

Free article

Abstract

The biogenesis of multipass membrane proteins challenges the endoplasmic reticulum (ER) quality control, particularly when transmembrane segments contain polar or charged residues required for function. Fks1, the catalytic subunit of yeast β-(1,3)-glucan synthase, exemplifies this challenge because its large multipass transmembrane architecture must support glucan synthesis at the plasma membrane while also undergoing efficient biogenesis in the ER. Here, we investigate the cellular role of PBR1 (YNL181W), an essential gene whose role remains uncharacterized even though its predicted product has similarity to oxidoreductases. By integrating quantitative morphological profiling with global genetic interaction analysis, we found that PBR1 function converges on cell-wall biosynthesis and closely parallels that of FKS1. Partial loss of Pbr1 function caused temperature-sensitive growth defects but also impaired β-(1,3)-glucan synthesis, and weakened cell-wall integrity. Under these conditions, Fks1 failed to accumulate at the cell surface and, instead, accumulated in ER-associated compartments, where it exhibited reduced stability. Biochemical analyses revealed the accumulation of immature Fks1 species, including forms defective in glycosylation, consistent with compromised ER quality control. A spontaneous missense suppressor allele of FKS1 partially restored Fks1 stability and growth, supporting a functional relationship between the two proteins. Pbr1 is a cytosol-facing ER membrane protein that physically associates with Fks1, and structural modeling suggests that it adopts a Rossmann-like fold capable of binding pyridine nucleotides despite divergence from canonical catalytic motifs. Together, these findings identify Pbr1 as an ER-associated, chaperone-like factor required for the folding and maturation of Fks1.

Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess

Marc Prentki  ¹ , Christopher J Nolan  ² , David E James  ³ , Bernard Thorens  ⁴ , Christopher J Rhodes  ⁵ , Barbara E Corkey  ⁶ , Charlotte Ling  ⁷ , Philippe Froguel  ⁸ , Chantal Mathieu  ⁹ , Jean-François Gautier  ¹⁰ , Marc Y Donath  ¹¹

Affiliations

• PMID: 42413493
• DOI: 10.1016/j.cmet.2026.06.012

Abstract

Obesity-related type 2 diabetes (T2D) is currently defined by insulin resistance and impaired insulin secretion. Sulfonylureas, thiazolinediones, and insulin are effective at lowering glycemia yet have not consistently translated into improved long-term outcomes. In contrast, recent interventions often produce metabolic benefits that exceed expectations based on glucose lowering alone. These contrasting observations suggest that our understanding of T2D pathophysiology is incomplete. We propose that, in obesity-related prediabetes and early T2D, insulin resistance, attenuated glucose-stimulated insulin secretion, modest hyperglycemia, and glucosuria represent beneficial functional changes in response to nutrient excess. These allostatic adaptive responses limit glucose flux into metabolically vulnerable tissues and reduce nutrient stress (nutri-stress). From this perspective, T2D is not simply a failure of glucose regulation but a coordinated systemic allostatic response to chronic energy excess aimed at preserving metabolic homeostasis. Therapeutic success may depend not only on lowering glycemia but also on how interventions alter tissue-specific glucose handling and metabolic stress.

Genetic suppressors as new therapeutic targets for Mendelian diseases

Claire Paltenghi-Peceva  ¹ , Sabine van Schie  ² , Erfan Heidari  ¹ , Stephen Friend  ³ , Jolanda van Leeuwen  ⁴

Affiliations

• PMID: 42392954
• DOI: 10.1016/j.tig.2026.06.003

Abstract

Most Mendelian diseases lack effective treatments, with current options often limited to symptomatic care rather than addressing the underlying genetic defect. In this opinion article, we argue that genetic suppressors, a specific class of modifier variants that can counteract the effects of disease-causing mutations, can identify promising new avenues for therapeutic intervention. We discuss the prevalence of potential suppressors across Mendelian diseases, describe approaches for their systematic identification, and consider their therapeutic relevance. As genome-wide screening technologies and machine learning methods continue to advance, we expect suppressor identification to accelerate in the near future. These suppressors present exciting opportunities for expanding our therapeutic arsenal and improving outcomes for individuals with inherited disorders.