APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin

• Published in: Cell reports (Cambridge) 2020-03, Vol.30 (11), p.3821-3836.e13
• Main Authors: Uzureau, Sophie, Lecordier, Laurence, Uzureau, Pierrick, Hennig, Dorle, Graversen, Jonas H., Homblé, Fabrice, Mfutu, Pepe Ekulu, Oliveira Arcolino, Fanny, Ramos, Ana Raquel, La Rovere, Rita M., Luyten, Tomas, Vermeersch, Marjorie, Tebabi, Patricia, Dieu, Marc, Cuypers, Bart, Deborggraeve, Stijn, Rabant, Marion, Legendre, Christophe, Moestrup, Søren K., Levtchenko, Elena, Bultynck, Geert, Erneux, Christophe, Pérez-Morga, David, Pays, Etienne
• Format: Article
• Language: English
• Subjects: Actomyosin; Actomyosin - metabolism; actomyosin cytoskeleton; Amino Acid Sequence; APOL1; APOL3; Apolipoprotein L1; Apolipoprotein L1 - chemistry; Apolipoprotein L1 - genetics; Apolipoprotein L1 - urine; Apolipoproteins L; Apolipoproteins L - metabolism; Calcium; Calcium - metabolism; Cell Line; Cellular Biology; Endoplasmic Reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Golgi Apparatus; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Golgi Apparatus - ultrastructure; Humans; kidney disease; Kidney Diseases; Kidney Diseases - metabolism; Kidney Diseases - urine; Kidney Glomerulus; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Life Sciences; Minor Histocompatibility Antigens; Minor Histocompatibility Antigens - metabolism; Mutation; Mutation - genetics; MYH9; NCS-1; Neuronal Calcium-Sensor Proteins; Neuronal Calcium-Sensor Proteins - metabolism; Neuropeptides; Neuropeptides - metabolism; Phenotype; Phosphatidylinositol Phosphates; Phosphatidylinositol Phosphates - metabolism; phosphoinositide control; Phosphotransferases (Alcohol Group Acceptor); Phosphotransferases (Alcohol Group Acceptor) - metabolism; PI4KB; Podocytes; Podocytes - drug effects; Podocytes - metabolism; Podocytes - ultrastructure; Poly I-C; Poly I-C - pharmacology; Potassium Channels; Potassium Channels - metabolism; Protein Binding; Protein Binding - drug effects; Protein Structure, Secondary; sleeping sickness
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.02.064

The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 can form K+ channels, but only APOL3 exhibits Ca2+-dependent binding of high affinity to neuronal calcium sensor-1 (NCS-1), promoting NCS-1-PI4KB interaction and stimulating PI4KB activity. Alteration of the APOL1 C-terminal helix triggers APOL1 unfolding and increased binding to APOL3, affecting APOL3-NCS-1 interaction. Since the podocytes of G1 and G2 patients exhibit an APOL1Δ or APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, with consecutive actomyosin reorganization of podocytes. [Display omitted] •C-terminal helix alteration unfolds APOL1, increasing APOL1 interaction with APOL3•APOL3 binds to NCS-1, promoting NCS-1-PI4KB interaction and PI4KB activation•C-terminal APOL1 variants interfere with APOL3-NCS-1 interaction, inactivating PI4KB•PI4KB inactivation occurs in podocytes from kidney disease patients with APOL1 variants Uzureau et al. propose a molecular explanation for the linkage between resistance to sleeping sickness and high risk of kidney disease in African individuals expressing APOL1 variants. These variants resist neutralization by T. rhodesiense SRA and kill the parasite, but they also indirectly trigger podocyte actomyosin reorganization through interaction with APOL3, inactivating the NCS-1-PI4KB complex.