Intracellular lipid surveillance by small G protein geranylgeranylation.

Imbalances in lipid homeostasis can have deleterious effects on health1,2. Yet how cells sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption remains unclear. Here we describe a mechanism for intracellular lipid surveillance in Caenorhabditis elegans that involves transcriptional inactivation of the nuclear hormone receptor NHR-49 through its cytosolic sequestration to endocytic vesicles via geranylgeranyl conjugation to the small G protein RAB-11.1. Defective de novo isoprenoid synthesis caused by lipid depletion limits RAB-11.1 geranylgeranylation, which promotes nuclear translocation of NHR-49 and activation of rab-11.2 transcription to enhance transporter residency at the plasma membrane. Thus, we identify a critical lipid sensed by the cell, its conjugated G protein, and the nuclear receptor whose dynamic interactions enable cells to sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption and lipid metabolism.

Isothermal titration calorimetry and vesicle leakage assays highlight the differential behaviors of tau repeat segments upon interaction with anionic lipid membranes.

Tau misfolding has been implicated in a variety of tauopathies, including Alzheimer's disease. The microtubule binding domain of tau consists of four repeat segments (R1-R4), and aggregation of these segments leads to the formation of neurofibrillary tangles. Previous studies indicate that misfolded tau associates with anionic phospholipid membranes, invoking structural transformations that could play a role in aggregation. Here, we investigated the role of membrane surface charge on the binding affinity of individual tau repeat segments, and whether these segments exhibit lytic activity. We quantified the thermodynamics of this process in terms of the affinity (Kd), enthalpy (ΔH), entropy (ΔS), and change in specific heat capacity (ΔCp). While neutral membranes exhibited weak interactions with each tau repeat segment, segments R2 and R3 exhibited relatively strong binding with anionic membranes with favorable ΔS and a negative value of ΔCp. Calcein leakage assays show that each repeat segment displays lytic activity, but only upon the interaction with anionic membranes. Taken together, these results distinguish the relative selectivity for anionic membranes by each repeat segment and the degree of membrane disruption that results.

Cytosolic dopamine determines hypersensitivity to blunt force trauma.

The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is conserved across species, from nematodes to humans. However, the molecular mechanisms underlying this hypersensitivity to blunt force trauma remain elusive. We find that extravesicular dopamine, a key driver of Parkinson's disease, extends its toxic role to the acute challenges associated with injury. Ectopic dopamine synthesis in serotonergic neurons sensitizes this resilient neuronal subtype to trauma-induced degeneration. While dopaminergic neurons normally maintain dopamine in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Cytosolic dopamine accumulation, through perturbations to its synthesis, metabolism, or packaging, is necessary and sufficient to drive neurodegeneration upon injury and during aging. Additionally, degeneration is further exacerbated by rapid upregulation of the rate-limiting enzyme in dopamine synthesis, cat-2, via the FOS-1 transcription factor. Fundamentally, our study in C. elegans unravels the molecular intricacies rendering dopaminergic neurons uniquely prone to physical perturbation across evolutionary lines.

Reduced bone morphogenic protein signaling along the gut-neuron axis by heat shock factor promotes longevity.

Aging is a complex and highly regulated process of interwoven signaling mechanisms. As an ancient transcriptional regulator of thermal adaptation and protein homeostasis, the Heat Shock Factor, HSF-1, has evolved functions within the nervous system to control age progression; however, the molecular details and signaling dynamics by which HSF-1 modulates age across tissues remain unclear. Herein, we report a nonautonomous mode of age regulation by HSF-1 in the Caenorhabditis elegans nervous system that works through the bone morphogenic protein, BMP, signaling pathway to modulate membrane trafficking in peripheral tissues. In particular, HSF-1 represses the expression of the neuron-specific BMP ligand, DBL-1, and initiates a complementary negative feedback loop within the intestine. By reducing receipt of DBL-1 in the periphery, the SMAD transcriptional coactivator, SMA-3, represses the expression of critical membrane trafficking regulators including Rab GTPases involved in early (RAB-5), late (RAB-7), and recycling (RAB-11.1) endosomal dynamics and the BMP receptor binding protein, SMA-10. This reduces cell surface residency and steady-state levels of the type I BMP receptor, SMA-6, in the intestine and further dampens signal transmission to the periphery. Thus, the ability of HSF-1 to coordinate BMP signaling along the gut-brain axis is an important determinate in age progression.

Loss of heat shock factor initiates intracellular lipid surveillance by actin destabilization.

Cells sense stress and initiate response pathways to maintain lipid and protein homeostasis. However, the interplay between these adaptive mechanisms is unclear. Herein, we demonstrate how imbalances in cytosolic protein homeostasis affect intracellular lipid surveillance. Independent of its ancient thermo-protective properties, the heat shock factor, HSF-1, modulates lipid metabolism and age regulation through the metazoan-specific nuclear hormone receptor, NHR-49. Reduced hsf-1 expression destabilizes the Caenorhabditis elegans enteric actin network, subsequently disrupting Rab GTPase-mediated trafficking and cell-surface residency of nutrient transporters. The ensuing malabsorption limits lipid availability, thereby activating the intracellular lipid surveillance response through vesicular release and nuclear translocation of NHR-49 to both increase nutrient absorption and restore lipid homeostasis. Overall, cooperation between these regulators of cytosolic protein homeostasis and lipid surveillance ensures metabolic health and age progression through actin integrity, endocytic recycling, and lipid sensing.