Intracellular lipid surveillance by small G protein geranylgeranylation

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

“…We observed that reducing and ablating DBL‐1 signaling in neural hsf‐1 transgenics and dbl‐1(nk3) mutants resulted in approximately a 2‐fold reduction in the transcription of several Rab GTPases with roles in regulating the early endosome (RAB‐5), late endosome (RAB‐7), basolateral exocytosis (RAB‐8), and endocytic recycling (RAB‐11.1) (Figure 4c and Figure ). Consistent with our previous study (Watterson et al, 2022), we detected transcriptional activation of the RAB‐11.1 paralog, rab‐11.2 , which likely occurs through loss of RAB‐11.1 expression and subsequent activation of the intracellular lipid surveillance response (Figure 4c and Figure ). Thus, reducing BMP/DBL‐1 signaling in the nervous system has the potential to modulate lipid surveillance and nuclear hormone receptor, NHR‐49, activity in the intestine.…”

“…(e) Relative fluorescence in Day 1 adult transgenic worms expressing SMA-6::GFP by large-particle flow cytometry. Mean with 95% confidence interval, ****p ˂ 0.0001 by an unpaired student's t-test, n = 1605 (control) and n = 2540 (rab-11.1 RNAi) over multiple trials ).Consistent with our previous study(Watterson et al, 2022), we detected transcriptional activation of the RAB-11.1 paralog, rab-11.2, which likely occurs through loss of RAB-11.1 expression and subsequent activation of the intracellular lipid surveillance response (Figure4cand FigureS4d). Thus, reducing BMP/ DBL-1 signaling in the nervous system has the potential to modulate lipid surveillance and nuclear hormone receptor, NHR-49, activity in the intestine.…”

“…Both the neuron‐specific ligand, DBL‐1, and its dedicated receptor in the intestine, SMA‐6, were required for lifespan extension by neural HSF‐1. We find that neural HSF‐1 represses dbl‐1 transcription thereby reducing BMP signal transduction in the intestine via a SMA‐3‐mediated negative feedback loop entailing the transcriptional repression of membrane trafficking regulators linked to intracellular lipid surveillance (Watterson et al, 2022 ). In turn, this reduces steady‐state protein levels of the SMA‐6 receptor and further dampens signal transduction.…”

“…See Table S1. (Watterson et al, 2022). In turn, this reduces steadystate protein levels of the SMA-6 receptor and further dampens signal transduction.…”

Prenylation Defects and Oxidative Stress Trigger the Main Consequences of Neuroinflammation Linked to Mevalonate Pathway Deregulation

“…It has been recently observed in Caenorhabditis elegans that intracellular lipid homeostasis depends on the sequestration of the nuclear hormone receptor NHR-49 into endosomes through a specific interaction with geranylgeranylated Rab11.1. Lipid depletion, and thus a reduced flux through the mevalonate pathway, reducing Rab11.1 geranylgeranylation, induces NHR-49 translocation to the nucleus and the activation of a transcription program that leads to increased nutrient absorption [ 50 ].…”