The Cell Biology of APOL1

Abstract

The association of variants in the APOL1 gene, which encodes apolipoprotein L1 (APOL1), with progressive nondiabetic kidney diseases in African Americans has prompted intense investigation into the function(s) of APOL1. APOL1 is an innate immune effector that protects human beings from infection by some trypanosomal parasites. We review the data characterizing APOL1 trypanolytic function, which has been a basis for studies of APOL1 function in mammalian cells. Subsequently, we discuss the studies that use animal models, mammalian cell culture models, and kidney biopsy tissue to discover the mechanisms of variant APOL1-associated kidney diseases.

Keywords: African American; Kidney disease; cytotoxicity; ion channel; trypanosome.

Figure 1. APOL1 localization and activities in the trypanosome has parallels in human cells

(A) APOL1 enters the trypanosome as a component of HDL3 particles via endocytosis at the flagellar pocket and is trafficked to the lysosome. Independent studies report different mechanisms of trypanosomal killing. Activation of the APOL1 channel activity within the lysosome has been reported to cause lysosomal swelling and trypanolysis. Others have found trypanolytic activity has localized to the plasma membrane, or the mitochondria. (B) Studies overexpressing APOL1 in human cells have reported that its expression leads to the movement of the transcription factor EB (TFEB) from the cytosol to the nucleus where it induces the transcription of genes necessary for the upregulation of lysosomal biogenesis and increases endosomal trafficking. The upregulation of these pathways contributes to the restriction of HIV-1 infection in this report. (C) Other investigators found that overexpressed APOL1-G1 and-G2, but not G0, can localize to the plasma membrane where it allows the efflux of potassium driving the phosphorylation and activation of p38 MAPK and inhibition of gp130-STAT3 signaling that may change the cells transcriptional program. Activation of the p38/STAT3 pathway downstream of channel activity at the plasma membrane was observed only after expression of the kidney disease risk variants of APOL1.

Figure 2. Trajectory of podocyte density change in FVB, Tg-G0 and Tg-G2 mice

Podocyte densities in wild-type, Tg-G0, and Tg-G2 mouse kidneys using a method developed by the Wiggins lab. Data used to construct these trend lines were reported in Bruggeman et al. In rodents and humans, once podocyte density decreases by 40%, glomerular disease becomes progressive. At 40d, podocyte densities were similar in FVB, Tg-G0 and Tg-G2 mice. Subsequently, podocyte density in the Tg-G2 mice were significantly lower but remained above the threshold for overt kidney disease through 300 days of age. We extrapolated the rate podocyte density change from the empirical data and found Tg-G2 mice would not be at risk for overt kidney disease within the normal lifespan of FVB/N mice, which is consistent with the observation that individuals with APOL1 risk genotypes are not destined to develop kidney disease in the absence of a “second hit” (e.g. HIV infection.