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The Mechanism of Kidney Disease Due to APOL1 Risk Variants

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The Mechanism of Kidney Disease Due to APOL1 Risk Variants PERSPECTIVE www.jasn.org The Mechanism of Kidney Disease Due to APOL1 Risk Variants Etienne Pays Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, Gosselies, Belgium JASN 31: 2502–2505, 2020. doi: https://doi.org/10.1681/ASN.2020070954 The apoL1 C-terminal variants G1 and PI4KB, because autophagy and mito- induced by the viral mimetic poly(I:C) G2 are linked to CKD.1 Expression of chondrial fission are dependent on the is linked to apoL1 involvement in these variants induces effacement of po- transfer of PI4KB-containing vesicles apoptosis.2,5 It is tempting to propose docyte foot processes, leading to the loss carrying the autophagy marker ATG9A that, as occurs for apoptotic Bcl2 of these cells from glomeruli and impair- from the Golgi to the endoplasmic retic- proteins,9 apoL oligomerization re- ment of the blood filtration activity of ulum (ER).4,6,7 sulting from high protein expression the kidney. A characteristic of G1/G2- Thus, podocyte dysfunctions could triggers the formation of mitochon- linked disease is the strong association result from interference of apoL1 G1/ drial megapores.10 As occurs for Bcl2 of glomerular pathology with the type I G2 variants with PI4KB activity. This homologous antagonist killer (Bak) IFN inflammatory response, such as oc- conclusion differs from that of many or Bcl2–associated X (Bax), hydro- curs with viral infection.1 studies, which have concluded that G1 phobic residues exposed on apoL1 he- In podocytes, either truncation of the and G2 induce nonspecificcytotoxicity.1 lices may contribute to generate lipidic C-terminal helix of apoL1 or deletion of Whereas some observed dysfunction membrane pores by surface interaction apoL3 similarly induces reorganization traits could be explained by PI(4)P re- with cardiolipin (CL).4,9 of actomyosin activity, resulting in a re- duction (altered vesicular trafficking c In podocytes, intracellular apoL1 is duction of their cellular size and adher- and mitochondrial activity, for in- processed differently from the se- ence, and an increase of motility.2 This stance), I argue that cytotoxicity could creted version of this protein (isoform phenotype is linked to a reduction of only result from an experimental in- 1).2 ApoL1 isoform 3, which is en- Golgi phosphatidylinositol-4-phosphate crease of natural apoL1 levels. [PI(4)P] levels, suggesting inactivation of coded by a transcript variant, is not targeted to the secretory pathway, but the Golgi phosphatidylinositol 4-kinase c Either in natural G1 or G2 podocytes, PI4KB. In various podocyte lines derived or in genetically edited podocytes ex- resides at the cytoplasmic face of the ER, together with apoL3.2,11 In- from G1, G2, or G1/G2 patients, signif- pressing C-terminal truncated apoL1 terestingly, this isoform lacks the exon icant reduction of Golgi PI(4)P levels has without change of gene expression 4 sequence, which exhibits strong cy- also been observed.2 ApoL3 was found to level, no sign of cytotoxicity was de- totoxicity when present in ectopically stimulate Golgi PI(4)P synthesis by tected.2 C-terminal apoL1 truncation expressed apoL1.12 PI4KB, and C-terminal apoL1 variants even induced a strongly reduced po- exhibit interaction with apoL3 due to in- tential for apoptosis, in striking con- c ApoL1-mediated cytotoxicity is re- 2 creased hydrophobicity. Thus, the trast with the induction of apoptosis ported to result from cationic pore for- apoL1 variants appear to inhibit the by ectopic G1 or G2 in various ex- mation at the plasma membrane.1,11,13 PI4KB-stimulating activity of apoL3 perimental settings. Because podocytes secrete apoL1 through apoL3 binding.2 The reduction of PI(4)P levels is c If overexpressed as occurs after ec- known to affect actomyosin activity topic expression, even wild-type and cellular mobility.3 Moreover, type I apoL1 triggers nonspecifictoxicity.8 Published online ahead of print. Publication date available at www.jasn.org. IFN strongly stimulates the expression This finding is in keeping with the of apoL1 and apoL3, and these proteins toxicity exhibited by wild-type apoL1 Correspondence: Dr. Etienne Pays, Laboratory of Molecular Parasitology, IBMM, Université Libre de are involved in the initiation of auto- when ingested in trypanosomes or Bruxelles, Gosselies, Belgium. Email: epays@ulb. phagy, mitochondrial fission, and apo- transfected in yeast or Escherichia coli.2 ac.be 2,4,5 ptosis. Such activities may depend In this respect, it is worth noting that Copyright © 2020 by the American Society of on the apoL3-mediated control of the strong increase of apoL1 expression Nephrology 2502 ISSN : 1046-6673/3111-2502 JASN 31: 2502–2505, 2020 www.jasn.org PERSPECTIVE Figure 1. ApoL1 G1- or G2-mediated inhibition of apoL3 can explain kidney disease. ApoL3 controls PI(4)P synthesis by PI4KB.2 Under normal conditions, inhibition of PI4KB at the trans-Golgi network triggers reorganization of actomyosin-driven vesicular trafficking (hit 1). Under starvation or inflammatory conditions like viral infection, induction of autophagy and mitochondrial fission occur through actomyosin-driven transfer of PI4KB-carrying ATG9A vesicles from the Golgi to the ER, coupled with the reciprocal transfer of the PI(4)P phosphatase Suppressorofactin(Sac1)fromtheERtotheGolgi.4,6,7,26,27 Thus, the site of PI(4)P synthesis moves from the Golgi to the ER to trigger expansion of autophagy membranes rather than expansion of vesicular membranes. Inhibition of PI4KB at the ER-mitochondrion contact sites (MERCs) interferes with initiation of autophagy and mitochondrial membrane fusion/fission activities, preventing autophagy-mediated rescue from infection damage (hit 2). NM2A, nonmuscle myosin 2A, strongly associated with apoL1 and apoL3.2 isoform 1, it is not surprising to find c In accordance with the phenotype c The fact that kidney disease results this isoform in the secretory pathway expected after PI(4)P reduction, kid- from actomyosin reorganization is in and on the cell surface.11 However, ney disease induced by apoL1 variants line with the induction of this disease given its dependence on acidic pH for in transgenic mice involves modifica- after mutations in actomyosin com- membrane insertion, in order to gen- tions of podocyte vesicular trafficand ponentssuchasthoseinvolvedin erate surface pores apoL1 must travel autophagy.17 mitochondrial fission.20 Given the through the endocytic pathway and be particular cytoskeleton constraints fi recycled back to the plasma mem- c Signi cantly reduced levels of PI(4)P required for the biology of podo- brane.14 Because independent studies were measured not only in various po- cytes, such as the architecture of foot did not detect apoL1 in the endocytic docytes expressing C-terminal apoL1 processes, the high susceptibility of pathway, this hypothesis can be ruled variants, but also in glomeruli of kidney these cells to actomyosin changes can out.2,11,15 Moreover, if apoL1 recycling biopsies from human G1 or G2 patients.2 readily be explained. totheplasmamembranecantenta- c fi tively be envisaged to explain try- In line with observations regarding c The increased mitochondrial s- panosome lysis,14 this process is PI(4)P reduction in podocytes, kidney sion observed after either apoL3 difficult to justify in podocytes, and disease is not only genetically linked to inactivation or deletion2 strikingly does not explain why the G1 or G2 apoL1 G1 and G2, but also to natural parallels the spectacular inhibition variants would trigger toxic pore ac- apoL3 knockout.18 The podocyte of mitochondrial fission observed in tivity.13 Conversely, reducing Golgi dysfunction phenotype resulting from trypanosomes with ingested apoL1,10 PI(4)P levels can affect cation trans- apoL3 knockout in either podocyte proving that apoL1 or apoL3 can con- port at the cell surface.16 lines or human individuals cannot be trol mitochondrial fusion/fission in explained by the cytotoxicity of apoL1 quite distinct cellular types. Accord- I propose that kidney disease results variants. ingly, the G1 and G2 variants, but not from cellular reorganization induced by wild-type apoL1, trigger mitochondrial apoL1-mediated inactivation of apoL3 c The proposed pathogenic effect of fission.21 Given the importance of CL that, via PI4KB, controls both vesicular increased hydrophobicity in apoL1 and phosphatidic acid in mitochon- trafficking at the Golgi (Figure 1, hit 1) variants easily explains the puzzling drial fission or fusion,22 the strong and membrane fusion activities at ER– observation that the recruitment of binding of apoL1 and apoL3 to both mitochondrion contact sites (MERCs) these variants to lipid droplets atten- lipids2,4 is likely to be involved in the (Figure 1, hit 2). uates the effects of G1/G2.19 control of this activity. JASN 31: 2502–2505, 2020 ApoL3 Inhibition by ApoL1 Variants 2503 PERSPECTIVE www.jasn.org c Mitochondrial fission can be involved FUNDING 10. Vanwalleghem G, Fontaine F, Lecordier L, in autophagy.23,24 The binding of Tebabi P, Klewe K, Nolan DP, et al.: Coupling of lysosomal and mitochondrial membrane apoL3 to mitochondrial phosphatidic This work was financially supported by the permeabilization in trypanolysis by APOL1. European Research Council grant 669007-APOLs. acid and CL could promote mem- Nat Commun 6: 8078, 2015 brane fusion required for phagophore 11. Scales SJ, Gupta N, De Mazière AM, extension.24 apoL3 also stimulates Posthuma G, Chiu CP, Pierce AA, et al.: PI4KB, which triggers the initiation of Apolipoprotein L1-specificantibodiesdetect ACKNOWLEDGMENTS autophagy.6 Presumably due to the endogenous APOL1 inside the Endoplasmic reticulum and on the plasma membrane of low renewal rate of podocytes, in- J Am Soc Nephrol – The content of this article reflects the personal podocytes. 31: 2044 2064, terference with autophagy is ex- experience and views of the author(s) and should 2020 pected to exacerbate the pathology not be considered medical advice or recommen- 12. Khatua AK, Cheatham AM, Kruzel ED, of kidney disease.25 Indeed, the dations.
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