Chatterjee Bhaskar K, Alam Maroof, Chakravorty Arghya, Lacy Shannon M, Rech Jason, Brooks Charles L, Arvan Peter D, Truttmann Matthias C
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Internal Medicine- Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA.
bioRxiv. 2024 Jul 16:2024.07.13.603377. doi: 10.1101/2024.07.13.603377.
The AMP transferase, FICD, is an emerging drug target finetuning stress signaling in the endoplasmic reticulum (ER). FICD is a bi-functional enzyme, catalyzing both AMP addition (AMPylation) and removal (deAMPylation) from the ER resident chaperone BiP/GRP78. Despite increasing evidence linking excessive BiP/GRP78 AMPylation to human diseases, small molecules to inhibit pathogenic FICD variants are lacking. Using an high-throughput screen, we identify two small-molecule FICD inhibitors, C22 and C73. Both molecules significantly inhibit FICD-mediated BiP/GRP78 AMPylation in intact cells while only weakly inhibiting BiP/GRP78 deAMPylation. C22 and C73 also efficiently inhibit pathogenic FICD variants and improve proinsulin processing in β cells. Our study identifies and validates FICD inhibitors, highlighting a novel therapeutic avenue against pathologic protein AMPylation.
AMP转移酶FICD是一种新兴的药物靶点，可对内质网（ER）中的应激信号进行微调。FICD是一种双功能酶，可催化内质网驻留伴侣BiP/GRP78的AMP添加（AMP化）和去除（去AMP化）。尽管越来越多的证据表明过量的BiP/GRP78 AMP化与人类疾病有关，但缺乏抑制致病性FICD变体的小分子。通过高通量筛选，我们鉴定出两种小分子FICD抑制剂C22和C73。这两种分子均能显著抑制完整细胞中FICD介导的BiP/GRP78 AMP化，而对BiP/GRP78去AMP化的抑制作用较弱。C22和C73还能有效抑制致病性FICD变体，并改善β细胞中的胰岛素原加工。我们的研究鉴定并验证了FICD抑制剂，突出了一条针对病理性蛋白质AMP化的新治疗途径。
