摘要：SummaryTwo variants at theAPOL1gene, encoding apolipoprotein L1, account for more than 70% of the increased risk for chronic kidney disease in individuals of African ancestry. While the initiating event for APOL1 risk variant cell injury remains to be clarified, we explored the possibility of blocking APOL1 toxicity at a more upstream level. We demonstrate that deletion of the first six amino acids of exon 4 abrogates APOL1 cytotoxicity by impairing APOL1 translocation to the lumen of ER and splicing of the signal peptide. Likewise, in orthologous systems, APOL1 lethality was partially abrogated in yeast strains and flies with reduced dosage of genes encoding ER translocon proteins. An inhibitor of ER to Golgi trafficking reduced lethality as well. We suggest that targeting the MSALFL sequence or exon 4 skipping may serve as potential therapeutic approaches to mitigate the risk of CKD caused by APOL1 renal risk variants.Graphical abstractDisplay OmittedHighlights•Deletion of the first six amino acids of exon 4 (ΔMSALFL) abrogates APOL1 toxicity•ΔMSALFL impairs APOL1 translocation to the ER lumen and splicing of signal peptide•Impaired ER translocation and ER to Golgi trafficking reduced APOL1 toxicity•MSALFL sequence targeting or exon 4 skipping could yield possible therapyCellular physiology; Cell biology; Functional aspects of cell biology
