Incomplete functional divergence drives MADS-box gene synergy during floral development in tomato

Natalia Gaarslev  ^{1   2} , Ying Xu  ¹ , Eléonore Lizé  ^{1   2} , Irene Julca  ^{3   4} , Natasha Glover  ^{3   4} , Sebastian Soyk  ^{1   2}

Affiliations

• PMID: 42611900
• PMCID: PMC13506103
• DOI: 10.1371/journal.pbio.3003946

Abstract

Genetic synergy arises from interactions between functionally related genes that control complex traits in plants and animals. Synergy occurs when the combined effect of multiple genes exceeds the additive contribution from each individual gene. However, genetic mechanisms that drive and maintain synergy remain underexplored. Here, we investigated synergistic interactions among SEPALLATA (SEP) MADS-box genes during floral development in tomato. We discovered that SEP gene synergy emerges from duplicated genes that partitioned functions to regulate inflorescence architecture and floral organ identity. Moreover, synergistic interactions are reflected in non-additive expression changes that coordinate successive developmental stages. Finally, we demonstrate that SEP gene synergy occurred due to residual redundancy on the dose-sensitive FALSIFLORA/ANANTHA (FA/AN) module guiding floral identity. These results indicate that SEP gene synergy emerged as a consequence of incomplete functional divergence under gene dosage constraints. Our work provides insights into mechanisms through which gene families diverge to produce the substrate for biological innovations during evolution.

Tmem117, an oligodendrocyte-enriched regulator of NCX activity, links myelin homeostasis to counterregulation and metabolic health

Melvin Alappat ^{#  1   2} , Marta Anna Mazurkiewicz ^{#  1   2} , Iris Zambounis  ¹ , Alice Mastrangelo  ¹ , Vicente Mario Algaba Martínez  ^{1   3} , Thomas Grampp  ¹ , Francesco Prisco  ⁴ , Anja Kipar  ⁴ , Alexandre Picard  ⁵ , Musadiq A Bhat  ¹ , Dietmar Benke  ¹ , Hanns Ulrich Zeilhofer  ^{1   2   6} , Bernard Thorens  ⁵ , Sevasti Gaspari  ^{1   2}

Affiliations

• PMID: 42623448
• PMCID: PMC13506024
• DOI: 10.1073/pnas.2530122123

Abstract

The counterregulatory response (CRR) to hypoglycemia-critically depending on pancreatic glucagon secretion-is a fundamental, evolutionarily conserved homeostatic mechanism orchestrated by the central nervous system (CNS) to ensure survival during glucose scarcity. Tmem117 was previously identified in a genetic screen as a potential hypothalamic regulator of CRR. Here, we reveal that Tmem117 is enriched in cells of the oligodendrocytic lineage and we characterize the contribution of oligodendrocytic Tmem117 in CRR. We show that depletion of Tmem117 from either all oligodendrocyte lineage cells or only mature oligodendrocytes leads to myelin deficits and male-specific defects in CRR. Furthermore, we reveal that transient, adult-onset depletion of Tmem117 in mature oligodendrocytes is sufficient to induce long-lasting metabolic imbalances in male mice, suggesting that defects in oligodendrocytes and myelin can affect peripheral glucose homeostasis. Mechanistically, we provide insights on the molecular mechanism of action of Tmem117 showing that it regulates intracellular calcium dynamics through its interaction with the sodium-calcium exchanger NCX1. Together, these results redefine our understanding of the cellular contributors to the CRR, highlight the importance of oligodendrocytes in systemic glucose regulation, and position Tmem117 as a promising molecular target for cell-specific manipulation of sodium-calcium exchanger (NCX) activity.

Temporal phosphoproteomics reveals key regulators of procoagulant COAT platelet generation

Lucas Veuthey  ¹ , Manfredo Quadroni  ² , Maxime Jan  ^{3   4} , Debora Bertaggia Calderara  ¹ , Cindy Pereira Portela  ¹ , Lucas A Gautier  ¹ , Durre Shehwar  ¹ , Alessandro Aliotta  ¹ , Lorenzo Alberio  ¹

Affiliations

• PMID: 42598628
• PMCID: PMC13471948
• DOI: 10.1016/j.bvth.2026.100181

Abstract

Procoagulant platelets play a major role in stabilizing the primary hemostatic plug formed by aggregated platelets. The intracellular signaling pathways driving the shift from an aggregatory to a procoagulant COAT platelet phenotype upon collagen plus thrombin stimulation are only partially elucidated. Aiming at identifying differentially phosphorylated proteins and potential regulators of the procoagulant response, we mapped time-dependent changes in the phosphoproteome of aggregatory vs procoagulant COAT platelets using a liquid chromatography-mass spectrometry-based temporal phosphoproteomics approach. Upon stimulation with convulxin (an agonist of the collagen receptor glycoprotein VI) and thrombin, we observed that all platelets rapidly increased their overall phosphorylation during the first minute. Afterward, aggregatory platelets maintained or further increased their phosphorylation levels, whereas procoagulant COAT platelets exhibited a progressive and marked decrease in phosphorylation. Notably, during the first minute after activation, before the phenotypic development of the procoagulant response, several ion channels (calcium, sodium, hydrogen, and chloride), proteins involved in receptor negative feedback loops, cyclic nucleotide-dependent regulatory proteins, GTPases, and key kinases were already differentially phosphorylated in procoagulant COAT vs aggregatory experimental conditions. At the onset of the procoagulant response (1-3 minutes after activation), some calcium channels, phosphatidylinositol transfer proteins, α2-adrenergic receptors, and proteins involved in intracellular and extracellular mechanisms regulating integrin αIIbβ3 functionality were also differentially phosphorylated. This study highlights the usefulness of assessing phosphorylation dynamics to identify very early phosphorylation events and to understand the rapid phenotypic switch from aggregatory to procoagulant COAT platelets. This approach identified several candidate proteins and mechanisms likely to initiate and modulate the procoagulant response.

Transferrin receptor 1 is required for efficient hepatitis E virus production

Nathalie Da Silva  ¹ , Angela Pollán  ¹ , Luca Truscello  ¹ , Manfredo Quadroni  ² , Darius Moradpour  ¹ , Jérôme Gouttenoire  ¹

Affiliations

• PMID: 42611942
• DOI: 10.1371/journal.ppat.1014484

Free article

Abstract

Hepatitis E virus (HEV) infection is a major cause of acute viral hepatitis worldwide. HEV is a positive-strand RNA virus encoding three open reading frames (ORFs). The ORF3 protein is a small membrane-associated protein essential for viral particle secretion; however, its precise role in the viral life cycle remains incompletely understood. Here, we performed immunoprecipitation followed by mass spectrometry to identify host proteins interacting with the HEV ORF3 protein. Candidate interactors were validated by co-immunoprecipitation, confirming physical interactions between ORF3 and cysteine-rich and transmembrane domain-containing protein 1 (CYSTM1), Ras-related protein Rab24, and transferrin receptor 1 (TfR1). Confocal microscopy demonstrated colocalization of all three host factors with ORF3 protein. Gene silencing and knockout revealed that each protein contributes to virus production, with TfR1 depletion producing the most pronounced effect. In cells harboring replicating HEV, TfR1 colocalized with the ORF2 (capsid) and ORF3 proteins at Rab11A-positive recycling endosomes. Silencing of TfR1 in primary human hepatocytes, followed by HEV RNA transfection or infection, confirmed its role in virus production, particularly in the assembly of infectious particles, consistent with its colocalization with the HEV ORF2 protein. Collectively, our proteomics-based analysis identifies TfR1, along with CYSTM1 and Rab24, as novel ORF3-interacting host factors required for efficient production of infectious HEV. These findings provide new insights into the role of ORF3 protein in viral assembly and highlight TfR1 as a key host factor in the HEV life cycle.