Knocking out the door to tunicamycin entry

Protein homeostasis within the endoplasmic reticulum (ER) is essential for cell viability, and its misregulation is implicated in a growing number of diseases, including Alzheimer's disease, diabetes, and cancer (1–3). Consequently, the pharmacological manipulation of this pathway is of broad scientific and clinical interest. A variety of drugs have been used to model specific types of stresses that impact protein folding in the ER. One of the most widely used is tunicamycin, a mixture of homologous compounds originally isolated from bacteria and found to have antibiotic and antiviral properties (4). Tunicamycin prevents the first committed step of N-linked glycosylation of proteins by DPAGT1 in the ER (5–7), which causes extensive protein misfolding and activation of the unfolded protein response (UPR). Despite its widespread use in the laboratory, the mechanism by which tunicamycin enters cells has remained a mystery. In PNAS, Reiling et al. (8) investigate the requirements for tunicamycin sensitivity in mammalian cells and identify MFSD2A as a putative plasma membrane transporter. To identify factors required for tunicamycin-induced death, Reiling et al. (8) use an insertional mutagenesis strategy in the near-haploid human cell …