Alteration of the lipid composition of biological membranes interferes with their function and can cause tissue damage by triggering apoptosis. Upon lipid bilayer stress, the endoplasmic reticulum mounts a stress response similar to the unfolded protein response. However, only a few genes are known to regulate lipid bilayer stress. We performed a suppressor screen that combined the auxin-inducible degradation (AID) system with conventional RNAi in C. elegans to identify members of the lipid bilayer stress response. AID-mediated degradation of the mediator MDT-15, a protein required for the upregulation of fatty acid desaturases, induced the activation of lipid bilayer stress-sensitive reporters. We screened through most C. elegans kinases and transcription factors by feeding RNAi. We discovered nine genes that suppressed the lipid bilayer stress response in C. elegans. These suppressor genes included drl-1/MAP3K3, gsk-3/GSK3, let-607/CREB3, ire-1/IRE1, and skn-1/NRF1,2,3. Our candidate suppressor genes suggest a network of transcription factors and the integration of multiple tissues for a centralized lipotoxicity response in the intestine. Thus, we demonstrated proof-of-concept for combining AID and RNAi as a new screening strategy and identified eight conserved genes that had not previously been implicated in the lipid bilayer stress response.

生物膜脂质组成的改变会干扰其功能，并可能通过触发细胞凋亡而引起组织损伤。在脂质双层压力作用下，内质网的压力反应类似于未折叠的蛋白质反应。然而，已知仅有少数基因可调节脂质双层压力。我们进行了抑制剂筛选，将线虫中的生长素诱导降解（AID）系统与常规RNAi相结合，以鉴定脂质双层应激反应的成员。AID介导的介体MDT-15的降解是脂肪酸双饱和酶上调的必需蛋白，MDT-15介导了脂质双层应激敏感报道分子的活化。我们筛选了大多数秀丽隐杆线虫进食RNAi的激酶和转录因子。我们发现了九种抑制秀丽线虫脂质双层应激反应的基因。这些抑制基因包括drl-1/ MAP3K3， gsk-3/ GSK3， let-607/ CREB3， ire-1/ IRE1，和 skn-1 / NRF1,2,3。我们的候选抑制基因表明，转录因子网络和多个组织的整合可在肠道内实现集中的脂毒性反应。因此，我们证明了将AID和RNAi结合起来作为新的筛选策略的概念验证，并鉴定了八个以前未参与脂质双层应激反应的保守基因。