Endoplasmic reticulum-translocation is essential for APOL1 cellular toxicity
Etty Kruzel-Davila,
Ira Bavli-Kertselli,
Ayala Ofir,
Amber M. Cheatham,
Revital Shemer,
Eid Zaknoun,
Sergiy Chornyy,
Orly Tabachnikov,
Shamara E. Davis,
Atanu K. Khatua,
Karl Skorecki,
Waldemar Popik
Affiliations
Etty Kruzel-Davila
Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of Genetics and Developmental Biology and Rappaport Faculty of Medicine and Research Institute, Technion—Israel Institute of Technology, Haifa, Israel
Ira Bavli-Kertselli
Department of Nephrology, Rambam Health Care Campus, Haifa, Israel
Ayala Ofir
Department of Nephrology, Rambam Health Care Campus, Haifa, Israel
Amber M. Cheatham
Meharry Medical College, Center for AIDS Health Disparities Research, Department of Microbiology and Immunology, 1005 D. B. Todd Boulevard, Nashville, TN 37028, USA
Revital Shemer
Departments of Genetics and Developmental Biology and Rappaport Faculty of Medicine and Research Institute, Technion—Israel Institute of Technology, Haifa, Israel
Eid Zaknoun
Departments of Genetics and Developmental Biology and Rappaport Faculty of Medicine and Research Institute, Technion—Israel Institute of Technology, Haifa, Israel
Sergiy Chornyy
Departments of Genetics and Developmental Biology and Rappaport Faculty of Medicine and Research Institute, Technion—Israel Institute of Technology, Haifa, Israel
Orly Tabachnikov
Department of Nephrology, Rambam Health Care Campus, Haifa, Israel
Shamara E. Davis
Meharry Medical College, Center for AIDS Health Disparities Research, Department of Microbiology and Immunology, 1005 D. B. Todd Boulevard, Nashville, TN 37028, USA
Atanu K. Khatua
Meharry Medical College, Center for AIDS Health Disparities Research, Department of Microbiology and Immunology, 1005 D. B. Todd Boulevard, Nashville, TN 37028, USA
Karl Skorecki
Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of Genetics and Developmental Biology and Rappaport Faculty of Medicine and Research Institute, Technion—Israel Institute of Technology, Haifa, Israel; Corresponding author
Waldemar Popik
Meharry Medical College, Center for AIDS Health Disparities Research, Department of Microbiology and Immunology, 1005 D. B. Todd Boulevard, Nashville, TN 37028, USA; Department of Internal Medicine, 1005 D. B. Todd Boulevard, Nashville, TN 37028, USA; Corresponding author
Summary: Two variants at the APOL1 gene, 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.
