Biology subjects

Hekman, R.

Publications and source records attributed to Hekman, R..

4 recordsLinked to original sources

bioRxiv2025

Progressive Remodeling of Global Protein Interaction Networks in a Mouse Model of Tauopathy

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present the first temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas identifies functionally validated assemblies--including MAPT-Dpysl2 and Cyfip1-actin complexes--that modulate early disease phenotypes in vivo. By revealing how phosphorylation tunes macromolecular complex architecture and function, this work reframes tauopathy as a disease of dynamic network instability, and establishes a generalizable framework for early detection and mechanistic dissection of neurodegeneration.

neuroscience↗

bioRxiv2024

Single-cell RNA-sequencing reveals immune system compartmentalization under symbiosis in the stony coral Oculina arbuscula

Many cnidarians host single-celled algae within gastrodermal cells, yielding a mutually beneficial exchange of nutrients between host and symbiont, and dysbiosis can lead to host mortality. Previous research has uncovered symbiosis tradeoffs, including suppression of immune pathways in cnidarians hosting intracellular algae and correlations between symbiotic state and pathogen susceptibility. Here, we used a multiomic approach to characterize symbiotic states of the facultatively symbiotic coral Oculina arbuscula by generating genotype-controlled fragments of symbiotic and aposymbiotic tissue. 16S metabarcoding showed no difference in bacterial communities between symbiotic states. Whole-organism proteomics revealed differential abundance of proteins related to immunity, confirming immune suppression during symbiosis. Finally, single-cell RNAseq identified diverse cell clusters within seven cell types across symbiotic states. Specifically, the gastrodermal cell clusters containing algal-hosting cells from symbiotic tissue had higher expression of nitrogen cycling and sugar transport genes than aposymbiotic gastrodermal cells. Furthermore, differential enrichment of immune system gene pathways and lower expression of genes involved in immune regulation were observed in these gastrodermal cells from symbiotic tissue. However, no differences in immune gene expression in the immune cell cluster were observed between symbiotic states. This work reveals a compartmentalization of immune system regulation in specific gastrodermal cells in symbiosis, which may limit symbiosis tradeoffs by simultaneously dampening immunity in algal-hosting cells while maintaining general organismal immunity.

genomics↗

bioRxiv2021

Inhibition of Mul1-mediated ubiquitination promotes mitochondria-associated translation

G-Protein Pathway Suppressor 2 (GPS2) was recently identified as an endogenous inhibitor of non-proteolytic ubiquitination mediated by the E2 ubiquitin-conjugating enzyme Ubc13. GPS2-mediated restriction of K63 ubiquitination is associated with the regulation of insulin signaling, inflammation and mitochondria-nuclear communication, however a detailed understanding of the targets of GPS2/Ubc13 activity is currently lacking, Here, we have dissected the GPS2-regulated K63 ubiquitome in mouse embryonic fibroblasts and human breast cancer cells, unexpectedly finding an enrichment for proteins involved in RNA binding and translation. Characterization of putative targets, including the RNA-binding protein PABPC1 and translation factor eiF3m, revealed a strategy for regulating the mitochondria-associated translation of selected mRNAs via Mul1-mediated ubiquitination. Our data indicate that removal of GPS2-mediated inhibition, either via genetic deletion or stress-induced nuclear translocation, promotes the ubiquitination of mitochondria-associated translation factors leading to increased expression of an adaptive antioxidant program. In light of GPS2 role in nuclear-mitochondria communication, these findings reveal an exquisite regulatory network for modulating mitochondrial gene expression through spatially coordinated transcription and translation.

cell biology↗

bioRxiv2019

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Triphenyl phosphate (TPhP) is an environmental PPAR{gamma} ligand, and growing evidence suggests that it is a metabolic disruptor. We have shown previously that the structurally similar ligand, tributyltin, does not induce brite adipocyte gene expression. Here, using in vivo and in vitro models, we tested the hypothesis that TPhP is a selective PPAR{gamma} ligand, which fails to induce brite adipogenesis. C57BL/6J male mice were fed either a low or very high fat diet for 13 weeks. From weeks 7-13, mice were injected intraperitoneally, daily, with vehicle, rosiglitazone (Rosi), or TPhP (10 mg/kg). Compared to Rosi, TPhP did not induce expression of browning-related genes (e.g. Elovl3, Cidea, Acaa2, CoxIV) in mature adipocytes isolated from inguinal adipose. To determine if this resulted from an effect directly on the adipocytes, 3T3-L1 cells and primary human preadipocytes were differentiated into adipocytes in the presence of Rosi or TPhP. Rosi, but not TPhP, induced expression of brite adipocyte genes, mitochondrial biogenesis and cellular respiration. Further, Rosi and TPhP induced distinct proteomes and phosphoproteomes; Rosi enriched more regulatory pathways related to fatty acid oxidation and mitochondrial proteins. We assessed the role of phosphorylation of PPAR{gamma} in these differences in 3T3-L1 cells. Only Rosi protected PPAR{gamma} from phosphorylation at Ser273. TPhP gained the ability to stimulate brite adipocyte gene expression in the presence of the CDK5 inhibitor and in 3T3-L1 cells expressing alanine at position 273. We conclude that TPhP is a selective PPAR{gamma} modulator that fails to protect PPAR{gamma} from phosphorylation at ser273.

pharmacology and toxicology↗