Evolution of the primate trypanolytic factor APOL1

Abstract

Significance African trypanosomes are parasites that can cause African sleeping sickness in humans. Humans and some primates, but not other mammals, have a gene called APOL1 that protects against certain trypanosomes. Genetic variants in APOL1 that arose in Africa are strongly associated with kidney disease in African Americans. These kidney disease-associated variants may have risen to high frequency in Africa because they can defend humans against a particularly pathogenic trypanosome. In this paper, we show how APOL1 has evolved by analyzing the distribution of these variants in Africa and then elucidating the molecular mechanisms that enhance their trypanosome killing capacity. We also show that these antitrypanosomal APOL1 variants may have adverse consequences for the host.

Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: Relevance to trypanosome lysis

“…These data are allied to a cytoplasmic-swelling model of trypanosome lysis that is contingent with endocytic recycling of APOL1 and the formation of cation-selective channels in the parasite plasma membrane. Confirmation of this model will require additional studies; nevertheless, the possibility that APOL1 generates cytolytic lesions in plasma membranes may inform speculation about the potential role of APOL1 in mediating human cell death (42), as well as hypotheses regarding the potential pathophysiological impact of human APOL1 variants that are associated with kidney disease (19,22).…”

“…1) (10, 18, 19). We speculate that this interaction prevents the acid-dependent membrane insertion of a putative transmembrane sequence (residues 332-354) (19), which could conceivably form part of a pH-gated channel or serve to anchor APOL1 in the membrane upon pH neutralization (Fig. 5).…”

“…Cytoplasmic swelling results from APOL1-induced sodium influx, as well as chloride influx via endogenous channels (24,25). In this model, membrane insertion of APOL1 is accomplished by three putative transmembrane sequences, one of which resides in the APOL1 C-terminal domain (19). The SRA protein of human serumresistant T. b. rhodesiense (oval), which is thought to be membraneanchored via a glycosylphosphatidylinositol group (not shown for clarity), is reported to cycle between the plasma membrane and the endocytic system, where it can bind to the C terminus of APOL1 at acidic pH (17).…”

“…Primate APOL1 orthologs, and two African human APOL1 variants, contain mutations in the C-terminal SRA-binding site that reduce binding affinity for SRA, allowing these variants to lyse SRA-producing trypanosomes (18)(19)(20). Two such human variants have been identified: the first, G1, is defined by two point mutations (S342G and I384M), one of which (I384M) was found to reduce binding affinity for SRA; the second, G2, is defined by a two-residue deletion (N388 and Y389) that prevents SRA binding (19).…”

“…Primate APOL1 orthologs, and two African human APOL1 variants, contain mutations in the C-terminal SRA-binding site that reduce binding affinity for SRA, allowing these variants to lyse SRA-producing trypanosomes (18)(19)(20). Two such human variants have been identified: the first, G1, is defined by two point mutations (S342G and I384M), one of which (I384M) was found to reduce binding affinity for SRA; the second, G2, is defined by a two-residue deletion (N388 and Y389) that prevents SRA binding (19). However, the G1-and G2-coding variants, found only among individuals of recent African ancestry, are strongly associated with chronic kidney disease in African Americans (20,21) and are thought to increase the propensity of APOL1 to cause tissue damage and human cell death (19,22).…”