Inhibition by misdirection

Abstract

Cell Biology The endoplasmic reticulum (ER) is the main entry point to the cellular secretory pathway. It is a major site of folding and quality control of newly synthesized proteins. When protein folding goes awry, the unfolded protein response (UPR) is activated to protect the cell from harmful effects of aberrant proteins. The UPR is triggered by an ER-tethered transcription factor, ATF6α. Small-molecule inhibitors known as Ceapins specifically inhibit ATF6α by retaining it at the ER. Torres et al. performed a genome-wide CRISPR interference screen to elucidate how Ceapins work. They found that Ceapins act via the ABCD3 peroxisomal transporter. In the presence of Ceapins, ABCD3 binds to ATF6α, which means the ER becomes tethered to peroxisomes and prevents ATF6α from leaving the ER and carrying out its function. eLife 8 , e46595 (2019).