CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBNmutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN–associated ID

Research priorities for rice pest management in tropical Asia: A simulation analysis of yield losses and management efficiencies

A simulation study was conducted to assess the current and prospective efficiency of rice pest management and develop research priorities for lowland production situations in tropical Asia. Simulation modeling with the RICEPEST model provided the flexibility required to address varying production situations and diverse pest profiles (bacterial leaf blight, sheath blight, brown spot, leaf blast, neck blast, sheath rot, white heads, dead hearts, brown plant-hoppers, insect defoliators, and weeds). Operational definitions for management efficacy (injury reduction) and management efficiency (yield gain) were developed. This approach enabled the modeling of scenarios pertaining to different pest management strategies within the agroecological contexts of rice production and their associated pest injuries. Rice pests could be classified into two broad research priority-setting categories with respect to simulated yield losses and management efficiencies. One group, including weeds, sheath blight, and brown spot, consists of pests for which effective pest management tools need to be developed. The second group consists of leaf blast, neck blast, bacterial leaf blight, and brown plant-hoppers, for which the efficiency of current management methods is to be maintained. Simulated yield losses in future production situations indicated that a new type of rice plant with high-harvest index and high-biomass production ("New Plant Type") was more vulnerable to pests than hybrid rice. Simulations also indicated that the impact of deployment of host resistance (e.g., through genetic engineering) was much larger when targeted against sheath blight than when targeted against stem borers. Simulated yield losses for combinations of production situations and injury profiles that dominate current lowland rice production in tropical Asia ranged from 140 to 230 g m. For these combinations, the simulated efficiency of current pest management methods, expressed in terms of relative yield gains, ranged from 0.38 to 0.74. Overall, the analyses indicated that 120 to 200 × 10 tons of grain yield are lost yearly to pests over the 87 × 10 ha of lowland rice in tropical Asia. This also amounts to the potential gain that future pest management strategies could achieve, if deployed