Sonic Hedgehog (SHH) signaling functions in temporal- and context-dependent manners to pattern diverse tissues during embryogenesis. The signal transducer Smoothened (SMO) is induced by sterols, oxysterols, and arachidonic acid (AA) through binding pockets in its extracellular cysteine-rich domain (CRD) and 7-transmembrane (7TM) bundle. In vitro analyses suggest SMO signaling is allosterically enhanced by combinatorial ligand binding to these pockets, but in vivo evidence of SMO allostery is lacking. Herein, we map an AA binding pocket at the top of the 7TM bundle and show that its disruption attenuates SHH- and sterol-stimulated SMO induction. A knock-in mouse model of compromised AA binding reveals that homozygous mutant mice are cyanotic, exhibit perinatal lethality, and display congenital heart disease. Surviving mutants demonstrate pulmonary maldevelopment and fail to thrive. Neurodevelopment is unaltered in these mice, suggesting that context-specific allosteric regulation of SMO signaling allows for precise tuning of pathway activity during cardiopulmonary development. Here, they identify a binding site on the Sonic Hedgehog signaling protein Smoothened for the allosteric regulator arachidonic acid (AA). A mutation that disrupts AA binding to this pocket compromises cardiopulmonary development.
M. Dillard, Christina A. Daly, Rojalin Pradhan et al.· Nature Communications· 0 citations
Synaptic vesicle cycling, if not properly constrained, can result in excessive neurotransmitter release and subsequent neural pathology. Rab GTPases orchestrate synaptic vesicle trafficking through GTP-dependent interactions with effector proteins, but the restraining mechanism of these interactions is unknown. Here we identify LRRC57 (or RABIN for RAB INhibitor), a conserved brain-enriched protein in glutamatergic synapses that binds multiple GTP-loaded synaptic Rabs and competitively blocks access to their effectors. Loss of Rabin increased glutamate release, expanded vesicle pools, accelerated vesicle turnover, and produced circuit hyperexcitability with epileptiform activity, which was mitigated by an antiepileptic agent that targets presynaptic function. Conversely, overexpression of the Rabin gene suppressed neurotransmitter release and protected against induced seizures and persistent epileptiform discharges. Together, these findings define a noncanonical decoy–effector mechanism that constrains presynaptic Rab signaling to preserve excitatory circuit stability.
Dušan Garić, Jonathan G. Murphy, B. J. Teubner et al.· bioRxiv· 0 citations
The study depicts an epigenetic polarity governing Treg-mediated immune tolerance, highlighting a fundamental asymmetry at the epigenetic level that differentially regulates Treg and conventional T cells.
Wenjun Huang, Yongqiang Feng, Jun Li et al.· Journal of Immunology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
