The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host–pathogen interactions

Abstract

Apolipoprotein L1 (APOL1) is a human protein that confers immunity to Trypanosoma brucei infections but can be countered by a trypanosome-encoded antagonist SRA. APOL1 belongs to a family of programmed cell death genes whose proteins can initiate host apoptosis or autophagic death. We report here that all six members of the APOL gene family (APOL1-6) present in humans have rapidly evolved in simian primates. APOL6, furthermore, shows evidence of an adaptive sweep during recent human evolution. In each APOL gene tested, we found rapidly evolving codons in or adjacent to the SRA-interacting protein domain (SID), which is the domain of APOL1 that interacts with SRA. In APOL6, we also found a rapidly changing 13-amino-acid cluster in the membrane-addressing domain (MAD), which putatively functions as a pH sensor and regulator of cell death. We predict that APOL genes are antagonized by pathogens by at least two distinct mechanisms: SID antagonists, which include SRA, that interact with the SID of various APOL proteins, and MAD antagonists that interact with the MAD hinge base of APOL6. These antagonists either block or prematurely cause APOL-mediated programmed cell death of host cells to benefit the infecting pathogen. These putative interactions must occur inside host cells, in contrast to secreted APOL1 that trafficks to the trypanosome lysosome. Hence, the dynamic APOL gene family appears to be an important link between programmed cell death of host cells and immunity to pathogens.

African origins and chronic kidney disease susceptibility in the human immunodeficiency virus era

“…It has been postulated that cellular and physiologic activities of apolipoprotein L1 include involvement in autophagic and apoptosis pathways [52,[77][78][79] . There is a general agreement that APOL1 expression occurs in podocytes [80] .…”

“…Apolipoprotein L1, a protein product of APOL1 gene is usually part of TLF circulating in the blood. The APOL1 gene is a member of the APOL gene family which is composed of six genes in humans (APOL1, APOL2, APOL3, APOL4, APOL5 and APOL6), grouped within 619kb on chromosome 22 [52] . This protein has five functional and structural domains: a secretory domain, pore forming domain, B-cell lymphoma 2 homology domain 3, membrane addressing domain, leucine zipper domain and serum resistant-associated interacting domain (SRA), listed from the N-terminal to C-terminal respectively.…”

Evolution of the primate trypanolytic factor APOL1

“…The APOL family has evolved rapidly during primate evolution (5). The APOL gene family on human chromosome 22 consists of six homologous genes in close proximity that arose through gene duplication.…”

APOL1 Localization in Normal Kidney and Nondiabetic Kidney Disease

“…APOL1 is restricted to the genomes of humans and some nonhuman primates. 10 Circulating APOL1 associates with HDL 3 particles and functions as a trypanolytic factor in human serum. 11,12 The parasite endocytoses APOL1-containing HDL particles, and once internalized, APOL1 is targeted to the lysosome, where its colicin-like pore-forming activity causes osmotic swelling of the lysosome and trypanosome death.…”