Biology subjects

Meservey, L. M.

Publications and source records attributed to Meservey, L. M..

3 recordsLinked to original sources

bioRxiv2025

Absence of MBP 3' UTR in Mice Disrupts mRNA Transport, Myelination, and Motor Learning

Myelin sheath maturation requires compaction, a cellular phenomenon mediated by local translation of myelin basic protein (MBP), which acts as a molecular zipper to join adjacent membranes and extrude the cytoplasm. Contrary to decades-old microinjection experiments indicating that Mbp mRNA transport is restricted to microtubules, we now show using smFISH that endogenous Mbp mRNA granules indeed localize along actin. To validate the in vivo necessity of Mbp mRNA transport and its dependence on the 3 UTR (untranslated region), we replaced the endogenous Mbp 3 UTR with polyA tail sequences. Though these mice have decreased Mbp mRNA levels, this alone could not account for their striking phenotypes - hypomyelination, baseline tremors, and motor learning defects. Thus, we cultured oligodendrocytes from these mice and found defects in both Mbp mRNA localization and local translation. These results demonstrate that the 3 UTR of a locally translated structural protein is critical for both developmental and activity-induced myelination.

cell biology↗

bioRxiv2025

Thermal proteome profiling identifies glucose binding proteins involved in metabolic disease

Recent work has shown that glucose can directly bind non-enzymatic proteins to modulate their function. We sought to build on this work by adapting thermal proteome profiling screens to uncover novel glucose interactors involved in metabolism. Proteome integral solubility alternation (PISA) profiling nominated 23 proteins with glucose-induced thermal solubility, including two proteins strongly implicated in metabolic disease, TSC22D4 and IGF2BP2. First, we characterized glucose binding of TSC22D4, an intrinsically disordered leucine zipper protein strongly implicated in hepatic steatosis. MST confirmed direct glucose-protein interaction of TSC22D4. UV-crosslinking mass spectrometry identified putative glucose binding at the C-terminal leucine zipper. Mutating isoleucine 322 to tryptophan (I322W) abolishes glucose binding. Crosslinking-MS and chemo-proteomic experiments suggest that glucose increases accessibility of the leucine zipper region, resulting in intra-protein contacts between C-terminal zipper domain and N-terminal intrinsically-disordered domain. TSC22D4 associates with fatty acid metabolism machinery proteins in response to high glucose conditions, suggesting a possible role for TSC22D4 in altering fatty acid metabolism. Next, we characterized glucose-binding in IGF2BP2, an RNA-binding protein essential for beta cell insulin secretion. We first confirmed direct IGF2BP2-glucose interaction and created glucose-binding mutant Y40A based on computational docking predictions. IGF2BP2Y40A exhibited a dominant negative impact on proliferation and insulin secretion in MIN6-6 beta cells. Glucose increased IGF2BP2 binding to client mRNAs Igf2 and Pdx1, which has previously been demonstrated to mediate its impact on insulin secretion. Thus, our data suggests that IGF2BP2 directly binds glucose to enhance insulin secretion.

biochemistry↗

bioRxiv2022

Glucose modulates transcription factor dimerization to enable tissue differentiation

Glucose is a universal energy currency for living organisms, however, its non-energetic functions in processes such as differentiation are undefined. In epidermis, differentiating cells exhibit dynamic changes in gene expression1-4 driven by specific transcription factors (TFs)5-9. The interplay between such TFs and biomolecules that also change in this process is not understood. Metabolomic analyses revealed that increased intracellular glucose accompanies differentiation of epidermal keratinocytes. This elevation also occurred in differentiating cells from other tissues and was verified in epidermal tissue engineered with glucose sensors, which detected a glucose gradient that peaked in the outermost differentiated layers. Free glucose accumulation, unaccompanied by its increased metabolism, was essential for epidermal differentiation and required GLUT1, GLUT3, and SGLT1 transporters. Glucose affinity chromatography and azido-glucose click chemistry uncovered glucose binding to diverse regulatory proteins, including the IRF6 TF, whose epidermal knockout confirmed its requirement in glucose-dependent differentiation. Direct glucose binding enabled IRF6 dimerization, DNA binding, genomic localization, and induction of IRF6 target genes, including essential pro-differentiation TFs GRHL1, GRHL3, HOPX and PRDM1. The IRF6R84C mutant found in undifferentiated cancers was unable to bind glucose. These data identify a new role for glucose as a gradient morphogen that modulates protein multimerization in cellular differentiation.

molecular biology↗