Biomolecular Sciences Seminar Series

Dr. Gant Luxton, University of California, Davis

Title: Nuclear Envelope Proteins Control Cytoplasmic Mechanics Through Organelles and Ribosomal Axes Disrupted in Aging and Disease

Abstract: Nuclear envelope proteins do far more than anchor the nucleus; they organize the cytoplasm. Using genetically encoded multimeric nanoparticles (GEMs) for passive nanorheology in living Caenorhabditis elegans, we discovered that GEMs diffuse ~10-fold more slowly in tissue cytoplasm than cultured yeast or mammalian cells, prompting us to ask what establishes this mechanical environment in vivo. Building a GEM-based tissue atlas across neurons, muscle, intestine, hypodermis, and germline revealed that each tissue maintains a distinct biophysical signature and we identified two independent mechanisms controlling these differences. First, ribosomes control macromolecular crowding. Second, the giant KASH protein ANC-1 (nesprin-1/2 ortholog) establishes cytoplasmic constraint through a LINC complex-independent function. ANC-1 also controls the positioning of ER, mitochondria, and lipid droplets, as well as ER and mitochondrial morphology. These two axes are separable: ribosomal crowding and organellar constraint can be independently tuned, providing cells with distinct mechanisms for adjusting their mechano-metabolic environment. Nuclear lamins connect to this framework through ribosome biogenesis. Emery Dreifuss muscular dystrophy-associatedlmn-1 mutations (R64P, Y59C) disrupt nucleolar density, reduce ribosome abundance, and collapse ER architecture, phenocopying ribosome depletion and establishing a nucleolar-ribosomal axis through which nuclear lamina defects propagate to cytoplasmic disorganization, providing a mechanistic basis for metabolic dysfunction in muscular dystrophy. Importantly, these mechano-metabolic axes deteriorate during physiological aging. Wild-type intestinal cytoplasm undergoes a dramatic mechanical transition at day 9 that correlates with motility decline and loss of ANC-1 accelerates this trajectory; mutants exhibit “aged” cytoplasmic mechanics from day 1, progressive functional decline, and shortened lifespan. Domain analysis reveals that actin-binding and spectrin-repeat domains govern longevity, while the transmembrane domain controls mechanics, demonstrating separable but essential functions. Together, our findings establish nuclear envelope proteins as mechano-metabolic integrators whose dysfunction drives both age-related decline and disease pathogenesis.

Host: Dr. Konrad Meister, Department of Chemistry and Biochemistry