Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease
Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills <i>Trypanosoma brucei</i> through induction of apoptotic-like parasite death, but two <i>T. brucei</i> clones...
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2024-10-01
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| author | Etienne Pays |
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| description | Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills <i>Trypanosoma brucei</i> through induction of apoptotic-like parasite death, but two <i>T. brucei</i> clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite. |
| format | Article |
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| publishDate | 2024-10-01 |
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| spelling | doaj-art-794afcd4b12c49a2a94602d1cb5f5a802025-08-20T02:11:12ZengMDPI AGCells2073-44092024-10-011320173810.3390/cells13201738Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney DiseaseEtienne Pays0Laboratory of Molecular Parasitology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, 6041 Gosselies, BelgiumApolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills <i>Trypanosoma brucei</i> through induction of apoptotic-like parasite death, but two <i>T. brucei</i> clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.https://www.mdpi.com/2073-4409/13/20/1738sleeping sicknesschronic kidney diseaseINF-I inflammationAPOL1 risk variantsN264K variantmembrane dynamics |
| spellingShingle | Etienne Pays Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease Cells sleeping sickness chronic kidney disease INF-I inflammation APOL1 risk variants N264K variant membrane dynamics |
| title | Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease |
| title_full | Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease |
| title_fullStr | Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease |
| title_full_unstemmed | Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease |
| title_short | Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease |
| title_sort | apolipoprotein l1 apol1 from sleeping sickness to kidney disease |
| topic | sleeping sickness chronic kidney disease INF-I inflammation APOL1 risk variants N264K variant membrane dynamics |
| url | https://www.mdpi.com/2073-4409/13/20/1738 |
| work_keys_str_mv | AT etiennepays apolipoproteinl1apol1fromsleepingsicknesstokidneydisease |