Biology subjects

Hetzer, M. W.

Publications and source records attributed to Hetzer, M. W..

4 recordsLinked to original sources

bioRxiv2023

Caloric restriction promotes beta cell longevity and delays aging and senescence by enhancing cell identity and homeostasis mechanisms.

Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. Here, we used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis link this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.

cell biology↗

bioRxiv2022

C-terminal disulfide bond in SUN2 regulate dynamic remodeling of LINC complexesat the nuclear envelope

The LINC complex tethers the cell nucleus to the cytoskeleton to regulate mechanical forces during cell migration, differentiation, and diseases. The function of LINC complexes relies on the interaction between highly conserved SUN and KASH proteins that form higher-order assemblies capable of load bearing. These structural details have emerged from in vitro assembled LINC complexes however, the principles of in vivo assembly remain obscure. Here, we report a conformation-specific SUN2 antibody as a tool to visualize LINC complex dynamics in situ. Using imaging, biochemical and cellular methods, we find that conserved cysteines in SUN2 undergo KASH dependent inter- and intra- molecular disulfide bond rearrangements. Disruption of the SUN2 terminal disulfide bond compromises SUN2 localization, turnover, LINC complex assembly as well as cytoskeletal organization and cell migration. Moreover, using pharmacological and genetic interventions, we identify components of the ER lumen as SUN2 cysteines redox state regulators. Overall, we provide evidence for SUN2 disulfide bond rearrangement as a physiologically relevant structural modification that regulates LINC complex functions.

cell biology↗

bioRxiv2021

Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress

AbstractDuring apoptosis, caspases degrade 8 out of [~]30 nucleoporins to irreversibly demolish the nuclear pore complex. However, for poorly understood reasons, caspases are also activated during cell differentiation. Here, we show that sublethal activation of caspases during myogenesis results in the transient proteolysis of four peripheral Nups and one transmembrane Nup. "Trimmed" NPCs become nuclear export-defective, and we identified in an unbiased manner several classes of cytoplasmic, plasma-membrane, and mitochondrial proteins that rapidly accumulate in the nucleus. NPC trimming by non-apoptotic caspases was also observed in neurogenesis and endoplasmic reticulum stress. Our results suggest that caspases can reversibly modulate nuclear transport activity, which allows them to function as agents of cell differentiation and adaptation at sublethal levels.

cell biology↗

bioRxiv2021

High-precision mapping of nuclear pore-chromatin interactions reveals new principles of genome organization at the nuclear envelope

The role of nuclear pore complexes (NPCs) in genome organization remains poorly characterized due to technical limitations in probing genome-wide protein-DNA interactions specific to the nuclear periphery. Here, we developed a new sensitive method, NPC-DamID, which combines in vitro reconstitution of nuclear import and DamID technology. The fixation-free method identifies chromatin interactions at the NPCs in intact nuclei from cells and tissues. We found that NPCs are preferentially associated with common and hierarchically arranged super-enhancers (SEs) across multiple cell types. We also uncovered phase-separated condensates at NPCs that compartmentalize and concentrate transcriptional coactivators and structural proteins at SE-regulated genes. Our results support NPCs as anchoring sites for SE regulatory hubs and cell-type-specific transcriptional control.

molecular biology↗